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Lithium Filtration for Improved Dose Penetration in BNCT


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Lithium Filtration for Improved Dose Penetration in BNCT

  1. 1. Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 5, pp. 1484 –1491, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter doi:10.1016/j.ijrobp.2006.11.022 CLINICAL INVESTIGATION Brain IMPROVED DOSE TARGETING FOR A CLINICAL EPITHERMAL NEUTRON CAPTURE BEAM USING OPTIONAL 6LI FILTRATION PETER J. BINNS, PH.D.,* KENT J. RILEY, PH.D.,* YAKOV OSTROVSKY, M.ENG.,* WEI GAO, M.S.,† J. RAYMOND ALBRITTON, M.S.,†‡ W. S. KIGER, III, PH.D.,‡ AND OTTO K. HARLING, PH.D.† *Nuclear Reactor Laboratory and †Department of Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA; and ‡Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Purpose: The aim of this study was to construct a 6Li 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 6Li 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 6Li 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. © 2007 Elsevier Inc. Boron neutron capture therapy, Epithermal neutrons, Neutron filter, Brain irradiation. INTRODUCTION Boron neutron capture therapy is a biochemically as well as physically targeted form of radiotherapy with the A new high-performance epithermal neutron beam facility potential to destroy tumor cells dispersed in normal tissue has been built at the Massachusetts Institute of Technology parenchyma, effectively providing radiosurgery at the (MIT) for clinical research into boron neutron capture ther- microscopic level. Dose conformity relies on the prefer- apy (BNCT). The facility provides a high-intensity, high- ential accumulation of boron in tumor combined with purity beam of collimated epithermal neutrons (En between achieving a homogeneous distribution of thermal neu- 1 eV and 10 keV) that enables irradiation to a brain toler- trons in the target volume. To aid tissue penetration, it is ance dose in approximately 10 min using boron compounds desirable to use an incident beam of somewhat higher currently approved for investigational use by the Food and energy (epithermal) neutrons that are then moderated Drug Administration (1). This beam has been used in clin- through elastic collisions in tissue. The low energy neu- ical trials for glioblastoma multiforme (GBM) and intracra- trons created at depth are captured more efficiently by 10 nial as well as metastatic melanoma although it is envisaged B nuclei. Epithermal neutron beams are invariably con- that other disease sites could be candidates for treatment taminated with photons and higher energy (intermediate once suitable boron delivery compounds are developed and and fast neutrons that are termed fast neutrons throughout approved (2). the text) neutrons that together with the nonselectively Reprint requests to: Peter J. Binns, Ph.D., Nuclear Reactor numbers DEFG02-96ER62193 and DE-FG02-97ER62489 and by Laboratory, 138 Albany Street, Cambridge, MA 02139. Tel: (617) the Harvard Joint Center for Radiation Therapy Foundation. 253-2099; Fax: (617) 258-5256; E-mail: Received Sept 8, 2006, and in revised form Nov 7, 2006. Conflict of interest: none. Accepted for publication Nov 9, 2006. Supported by the US Department of Energy under contract 1484
  2. 2. Improved dose targeting for BNCT using 6Li filtration ● P. J. BINNS et al. 1485 absorbed boron present in tissue produce an adventitious dose to the patient during irradiation. In the first approx- imation, beam design aims to minimize the background contamination while providing sufficient intensity and penetration to irradiate deep seated targets. Although this has been satisfactorily achieved with the fission converter beam (3, 4), possible improvements that are treatment or patient specific may further optimize delivery of thermal neutrons to the target volume with a particular field placement. During the phase I/II brain cancer trials con- ducted at Harvard-MIT that have studied toxicity of NCT, the prescription dose was first specified as the maximum dose to normal tissue (5) and subsequently as a whole brain average including the contoured tumor volume with treatment plans optimized to maximize dose to the tumor while respecting dose limits to other organs at risk such as skin, eyes, optic nerves, and optic chiasm Fig. 1. Schematic of the horizontal beam line for the fission converter– based epithermal neutron beam at the Massachusetts (6). In practice this requires multi-field plans to achieve Institute of Technology (MIT) research reactor (MITR II). The adequate coverage of the whole brain. Any option that beam line consists of an aluminum and polytetrafluoroethylene could improve neutron penetration to boost tumor dose at (PTFE; Teflon®) filter moderator as well as cadmium and lead or beyond the head centerline would be beneficial when filters. The housing for the lithium filter extends the existing beam tumor control and efficacy are studied more systemati- line by 18 mm and fits between the lead annulus housing the four beam monitors and the steel plate on to which the patient colli- cally. mator is mounted. Adding a 6Li filter to the neutron beam is a relatively simple and inexpensive modification that can increase the average energy of the epithermal neutrons in the beam and METHODS AND MATERIALS should improve neutron penetration at the expense of re- Epithermal neutron beam duced neutron intensity. Lithium-6 has a nuclear cross sec- The FCB provides a high intensity beam of epithermal neutrons tion that is inversely proportional to the speed of the inci- from a source of fission neutrons generated in a subcritical array of dent neutron and preferentially absorbs neutrons of lower uranium fuel that is housed in a separate vessel outside the reflec- energies to enhance the relative intensity of neutrons in the tor region of the reactor. The converter is driven by thermal higher part of the epithermal range without producing any neutrons from the reflector region surrounding the core of the MIT Research Reactor (MITR II), which currently operates at a maxi- significant undesired secondary radiation. A fixed 6Li filter mum power of 5 MW. A shielded horizontal beam line 2.5 m long has been incorporated previously at the Studsvik epithermal directs neutrons from the converter to the treatment room. The neutron facility in Sweden (7) that has proven to provide present configuration of the FCB is shown in Fig. 1. The fission improved penetration of the thermal neutron dose compo- neutrons emanating from the converter are moderated and filtered nent (8). Accommodating modifications such as additional by the D2O coolant, aluminum, fluorine, cadmium, and lead, beam filtration had been considered in the final design and resulting in a beam possessing a broad energy distribution of construction of the FCB although at that time inclusion of a epithermal neutrons with an average energy of approximately 2 6 Li filter was postponed (3). Following the initial clinical keV. The beam has minimal unwanted contamination from pho- trials using the FCB, a study was initiated to examine and tons (specific photon absorbed dose 3.5 0.5 10 13 Gy cm2) as well as fast (specific fast neutron absorbed dose 1.4 0.2 quantify the dosimetric advantages that using optional 6Li 10 13 Gy cm2) and thermal neutrons. This epithermal beam en- filtration could provide during therapy without significantly ergy distribution results in a thermal neutron maximum at a depth degrading the inherent beam characteristics and without in tissue of between 2 and 3 cm. Previous computational studies unduly limiting neutron intensity. using ideal, mono-energetic neutron beams showed that neutrons The feasibility of a 6Li filter was evaluated theoretically with energies between approximately 5 eV and 20 keV possess the using established Monte Carlo calculations of the beam line best depth dose characteristics for BNCT (10, 11). Neutrons out- and a mechanical design study was completed (9). A re- side this energy range are generally less useful since they contrib- movable filter in a sliding drawer assembly was constructed ute to the normal tissue dose without appreciably improving the and installed into the existing beam line, which required build-up of thermal flux at depth. The filtered beam enters a 1.1-m tapered portion of the beam line with lead walls that reflect some only minor modification. Dosimetric measurements were of the source neutrons (that might otherwise leave the beam) then performed to confirm the performance of the filter and toward the patient and forms a beam collimator. A circular cone to provide calibration data for treatment planning. Lastly shaped, 40 cm long final patient collimator constructed of lithiated some treatment plans from previously treated clinical cases and boronated epoxy mixed with Pb shot extends beyond the were evaluated with the new filter to show the tumor dose shielded beam line into the medical room to provide a beam that is enhancements that can be achieved. spatially and directionally well defined. Different circular field
  3. 3. 1486 I. J. Radiation Oncology ● Biology ● Physics Volume 67, Number 5, 2007 sizes are obtained by augmenting the collimator with additional end pieces that provide an epithermal flux at the patient position of approximately 5 109 n cm 2 s 1 with the converter operating at 83 kW (4). Four fission counters positioned in the periphery of the beam near the base of the patient collimator serve as integral monitors of the neutron fluence as it is delivered to the patient. Signals are fed to nuclear instrumentation modules (NIM) electronics and irradi- ations are administered with a programmable logic controlled (PLC) system that automatically terminates the irradiation when the integrated counts from the beam monitors reach the prescribed targets. Computational methods The beam line of the MIT FCB has been modeled in detail (12, 13) using the general purpose Monte Carlo transport code MCNP 4C (14) and was properly benchmarked by measurements for treatment planning purposes (1, 4, 15). This model was used for assessing the influence of the filter on beam performance for preliminary as well as final filter designs. Energy dependent weight windows were used for variance reduction and calculations were performed in several stages using surface source files written at Fig. 2. Schematic drawing of the lithium filter housing assembly various positions along the length of the beam line (12) to help that was designed to fit into the existing beam line. The numbered determine the best combination of filter thickness and location in components are as follows: (1) fixed steel holder, (2) sliding steel the beam line. Neutron and photon surface source files were holder, (3) boronated polyethylene shield ring, (4) aluminum filter written at the plane of the beam aperture. Fast neutron and photon housing, (5) roller bearing track, and (6) location of push rod absorbed dose rates (Dfn and D , respectively), epithermal (1 eV to switch. 10 keV) neutron flux ( epi), and the epithermal neutron current to flux ratio (J/ epi) were calculated in-air at the patient position. Flux tallies were integrated against photon and neutron kerma coeffi- aluminum ring with an outer diameter of 414 mm that is sealed cients (16) to determine the absorbed dose to brain tissue (17). The front and back between two thin (0.254-mm-thick aluminum) air beam was subsequently transported into an analytical model of the tight covers sealed by two graphite gaskets. This protects the water-filled ellipsoidal phantom (18), in which beam calibration lithium from exposure to air and oxidation. The filter holder was measurements were performed. Neutron fluxes and absorbed dose designed for convenient installation and removal of the filter and rates were calculated in 5 mm long cylindrical cells 12 mm in consists of a frame with surrounding shielding made from borona- diameter along the central axis of the beam. All calculations were ted polyethylene and steel that is fixed in the beam line. The beam normalized to a fission converter power of 83 kW. line was lengthened by 18 mm to accommodate the assembly. The holder, which operates like a vertical drawer, is split in two, allowing one side to slide out on two roller bearing tracks for Design and construction of lithium filter and holder insertion or removal of the filter, which is fastened to the drawer The initial design criteria were established from preliminary by screws in the three tabs visible in Figures 2 and 3. Once closed, calculations that showed a lithium filter 8 mm thick (95% enriched 6 the filter drawer is secured in place with a locking pin and, when Li) offered a reasonable compromise between improved penetra- the filter is installed, a push-rod switch is activated that interlocks tion and loss of beam intensity (9). Determining the best location with the automated dose monitoring and control system. for the filter in the beam line was also considered and an assembly that mounted between the lead annulus housing the 4 beam mon- itors and the steel plate attached to the patient collimator appeared the most expedient (Fig. 1). Consideration was given to placing the Measurement methods filter as far upstream as possible to reduce beam line activation Measurements of neutron flux were performed both in-air and in (and hence dose from photons incident upon the patient) from the an ellipsoidal water phantom on central axis for the 12- and 16-cm low energy neutrons it would absorb and to providing easy acces- diameter field sizes using bare and Cd covered gold foils (4). A sibility for routine installation and removal. A stringent series of lateral irradiation of the brain was simulated by the ellipsoidal safety analyses was also performed to ensure that there would be water phantom positioned with the smallest axis on the beam no undue concerns from tritium production and gas pressure on the center line (18). Absorbed dose rates were also determined using aluminum covers, nuclear heating from neutron absorption in the separate graphite and A-181 brain equivalent plastic walled ion- lithium as well as possible degradation of neutronic performance, ization chambers (IC-18s, Far West Technology, Goleta, CA), combustion or rapid oxidation. each with a sensitive volume of 0.1 cm3 to quantify respectively Based on these findings, an assembly was constructed and the photon and neutron absorbed dose components in the mixed installed, a schematic of which is presented in Fig. 2. The lithium radiation field (19). All measurements were performed with the filter consists of a disk 8 mm thick and 345 mm in diameter that is converter operating at between 58 and 80 kW (MIT research slightly greater in area than the neutron beam at its mounted reactor operating at 3.5 to 4.8 MW) and have been scaled to a position in the beam line. The lithium disc is pressed into an converter power of 83 kW.
  4. 4. Improved dose targeting for BNCT using 6Li filtration ● P. J. BINNS et al. 1487 biologically weighted dose to tumor and the maximum weighted dose to brain, was determined from the measured dose profiles as a function of depth in the water phantom. Treatment plan calculations A theoretical study was performed to assess the expected clin- ical performance of the filter for boronophenylalanine-fructose– mediated therapy by analysis of archived treatment plans for GBM patients treated using the epithermal neutron beam with the 12- cm-diameter field (6). Plans were prepared using the new MCNP model of the beam with and without the filter added. The beam models were benchmarked by comparing calculated and measured dose profiles in the ellipsoidal water phantom. Although the orig- inal treatments were planned using NCTPlan (15), these retrospec- tive treatments were planned using the radiotherapy planning system called MiMMC (Multi-Modal Monte Carlo) that is cur- rently being developed at the Beth Israel Deaconess Medical Fig. 3. The newly built removable 6Li filter assembly sits in a Center, with individual models constructed for each subject from drawer that easily slides into or out of the beam line upstream of CT images. The MCNP5 program version 1.40 was used for the patient collimator. The filter drawer (shown half withdrawn) is radiation transport and dose calculations (26). This version of secured in place with a locking pin and when installed activates a MCNP5 incorporates, as a standard feature, special modifications push-rod switch that interlocks with the automated dose monitor- for rapid calculations in lattice geometries that significantly accel- ing and control system. The beam line was lengthened 18 mm to incorporate the 6Li filter assembly. erate these treatment planning calculations (27, 28). In this anal- ysis the actual average blood concentration at the time of irradia- tion for each field was used. The same RBE and cRBE factors To compare the performance of the filter in the beam under described earlier were also used as biologic weighting factors in more realistic conditions pertinent to clinical irradiations of brain these treatment planning calculations. Tissue compositions for tumors, total biologically weighted dose profiles were determined brain and cranium used in transport calculations were from the for tissue and tumor from the measured data. The absorbed dose International Commission on Radiation Units and Measurements rates arising from thermal neutrons captured by boron were deter- (ICRU) Report 46 (29), with energy-dependent kerma coefficients mined from the product of the 2200 m s 1 neutron flux obtained adapted from ICRU and the National Institute of Standards and from the foil activation measurements (20, 21) and a kerma coef- Technology (NIST) by Goorley et al. (17). ficient of 8.66 10 8 Gy cm2 (17). Depth dose profiles were determined assuming boron concentrations of 18 and 65 g · g 1 in normal brain and diffuse tumor tissue, respectively, that approx- RESULTS imately represent the uptakes observed using boronophenylala- nine-fructose (BPA-F) (22). Biologically weighted depth dose Measurements and calculations profiles were then obtained by applying relative biological effec- Biologically weighted dose profiles as a function of depth tiveness (RBE) values of 1.0 for photons and 3.2 for thermal and for both normal tissue and tumor based on the measured and fast neutrons. Differences in the effective microdistribution of the calculated results in the ellipsoidal water phantom with the boron delivered by BPA in both tissue and tumor were also 6 Li filter installed for the 12-cm-diameter field aperture are accommodated using compound relative biological effectiveness shown in Fig. 4. These results are scaled to the converter (cRBE) factors of 1.3 for normal brain and 3.8 for tumor (23, 24). operating at 83 kW. The Monte Carlo simulations, based on The total biologically weighted dose is determined as the sum of the previously validated beam model, are depicted as curves the individual dose components (i.e., photon, fast neutron, thermal neutron, and boron) after weighting each with their respective RBE and have a statistical uncertainty of approximately 1% (1 ). or cRBE factors. Measurements are illustrated by data points with uncertain- The total weighted dose profiles obtained from the in-phantom ties of 4% for photons and between 13% and 22% for the measurements were then used to determine several figures of total neutron dose component, depending on the depth in merit, namely, the advantage parameters (25), to help quantify the tissue (19). Uncertainties in the boron dose are only attrib- changes in beam performance apparent with the filter. The advan- uted to errors associated with the thermal neutron flux tage depth (AD) is the depth at which the total weighted dose to determination, which are between 4% and 7%, depending tumor equals the maximum weighted dose received by normal on depth. No uncertainties are assessed for the applied tissue during an irradiation and is a measure of the maximum depth weighting factors. These depth profiles illustrate the con- at which therapeutic benefit is obtained. The advantage ratio (AR) ceptual advantage of BNCT with marked skin sparing, a is the ratio of the integral tumor dose to that of normal tissue averaged from the surface where the beam is incident to the dose build up to a maximum at a depth of approximately 3 advantage depth. The advantage depth dose rate (ADDR) specifies cm in normal tissue, and tumor doses that exceed the the therapeutic dose rate at the AD to give the total dose rate maximum normal tissue dose at all depths up to 9.9 cm (the achievable to treat tumor at the maximum useful depth of the beam advantage depth). The calculations, which include in the and is also the maximum absorbed dose rate to normal tissue. model of the beam line the filter assembly as it was actually Finally, the therapeutic ratio (TR), defined as the quotient of the built, are in good agreement with the measurements. Figure
  5. 5. 1488 I. J. Radiation Oncology ● Biology ● Physics Volume 67, Number 5, 2007 Fig. 4. Measured (points) and calculated (curves) biologically Fig. 5. Therapeutic ratio vs. depth determined from measurements weighted dose profiles produced in an ellipsoidal water phantom in the ellipsoidal water phantom with and without the 6Li filter in by the fission converter based epithermal neutron beam with an the fixed horizontal beam line of the fission converter beam (FCB) 8-mm-thick 6Li filter installed. The maximum dose to normal for the 12-cm-diameter aperture. The depth at which the therapeu- tissue is indicated. The advantage depth (AD) is where the tumor tic ratio curve crosses the horizontal line at unity is the maximum dose falls to the maximum normal tissue dose and the advantage useful penetration for therapy with the boron compound borono- depth dose rate (ADDR) is the dose rate to tumor at this depth. The phenylalanine-fructose in the FCB. advantage ratio (AR) is the ratio of the integral tumor dose to that in normal tissue averaged from the surface where the beam is incident to the AD. intensity compared with the open field, and this is the trade-off for improved penetration. Although beam intensity is attenuated by up to 52% for the 12-cm field, for example, 4 also indicates the various advantage parameters that re- irradiation times with the FCB are still clinically acceptable, flect the expected therapeutic effects in a realistic configu- as a weighted maximum normal tissue dose of 12.5 Gy can ration. A comparison between measured and calculated be delivered in a single field of approximately 22 min with figures of merit with the 6Li filter in the beam line is given the converter operating at 83 kW. This loss in beam inten- in Table 1. The estimated uncertainties for the predicted sity when using the filter will be largely recovered through advantage parameters are again small, being between 1% a combination of refueling the converter with fresh fuel, and 2%; those estimated for the measurements are 1% and which has already been completed and enables operation at 6% respectively for the AD and AR (8), and the measured 102 kW with the reactor at 5 MW, and a pending application ADDR has an uncertainty of 5%. Agreement between the with the US Nuclear Regulatory Commission to increase the predicted and measured values is good, as should be ex- MITR II operating power from 5 to 6 MW. pected, given the good agreement reported previously for The benefit of the 6Li filter to beam performance in the earlier configuration of the beam line without the filter improving penetration of the thermal neutrons is exempli- (4). Increased ADs of 10.0 and 9.9 cm are realized with the fied by the increase in therapeutic ratio at depth as shown in filter for the 16- and 12-cm fields respectively. The increase Fig. 5. The presence of the filter slightly reduces the max- of 6 mm for the 12-cm field is larger than the 3 mm for the imum TR attained at shallow depths where the value is 16-cm field and is qualitatively consistent with earlier pre- already high (TR 6.3), and shifts the peak in this curve 5 dictions when increasing neutron energy up to approxi- to 10 mm deeper to approximately 3 cm. Thereafter the TR mately a keV in a forward-directed beam (10). However, the for the 6Li filtered beam rises above that for the open beam, inclusion of the 8-mm-thick filter markedly reduces beam providing an AD of 9.9 cm that is 6 mm deeper than without Table 1. Comparison between measured and calculated (in parentheses) figures of merit with the 6 Li filter in the beam line Aperture diameter ADDR Time to reach 12.5 Gy (cm) AD (cm) AR (cGy min 1) (min) 16 10.0 (9.8) 5.5 (5.3) 64 (64) 19.5 (19.5) 16 (No filter) 9.7 5.9 159 7.9 12 9.9 (9.8) 5.7 (5.7) 55 (56) 22.7 (22.3) 12 (No filter) 9.3 6.0 114 11.0 Abbreviations: AD advantage depth; AR advantage ratio; ADDR advantage depth dose rate.
  6. 6. Improved dose targeting for BNCT using 6Li filtration ● P. J. BINNS et al. 1489 Fig. 6. Three field treatment plan for tumor dose calculated for both open (solid lines) and 6Li filtered (dotted lines) epithermal neutron beams shown in transverse, coronal and sagittal cross sections. The tumor is indicated by the dark blue contour. Both plans provide the same maximum biologically weighted dose to brain (12.1 Gy) that was given for the open field but the tumor coverage is improved at depth by using 6Li filtration. The doses assume a uniform distribution of boron and are biologically weighted (denoted by Gyw in the figure for emphasis). the filter and extends well beyond the midline of the average as compared with the plan with open beams. This is because sized head. the mean normal brain dose is also higher relative to the maximum dose at depth with the filtered beam. As shown in Treatment plans Fig. 7a, in all three cases, dose–volume histograms (DVHs) The advantage of incorporating the removable 6Li filter for the normal brain were very similar (5.0% reduction in for a planned treatment of a GBM is shown in Fig. 6. This maximum brain dose when the mean brain doses are example is a real case history from the last dose escalation matched), but the minimum tumor dose increased for the 6Li study performed at MIT, in which the patient presented with filtered beams. a right parietal GBM that was approaching the maximum Similar comparisons were performed for other cases, in allowable volume of 60 cm3 for inclusion in the trial. The which it became evident that inclusion of the 6Li filter did mean biologically weighted dose to normal tissue in the not always offer an advantage. As an illustration, Fig. 7b whole brain volume that includes the tumor was the pre- also shows DVHs for a patient with multifocal lesions who scription dose (7.7 Gy) with a maximum weighted dose to underwent irradiation in the same trial, but in the lower 7.0 normal brain of 12.5 Gy. The three-field treatment plan Gy mean brain dose cohort. In this case, the treatment plan delivered used the 12-cm diameter aperture with posterior- was recomputed for the open and filtered beams with the vertex, left-lateral, and right-lateral fields that were opti- same weights as originally used. Poorer tumor coverage mized with equal beam weightings. Biologically weighted (16% lower minimum dose) resulted for the shallow tumor isodose contours for tumor dose are shown in transverse, because, in this instance, the unfiltered beam had sufficient coronal, and sagittal views through the contoured tumor penetration to reach the relatively shallow target volume, volume. The boron concentrations assumed in normal brain whereas for the deeper tumor dose coverage was improved (19.3 g · g 1) and tumor (67.4 g · g 1) were based on marginally by 1.8%. Further optimization of the beam blood samples analyzed during therapy. Differences in the weights could not improve the tumor dose coverage with the 6 tumor isodose contours for the open and 6Li filtered beams Li filtered beams. are particularly apparent in transverse view, where, for example, the tumor volume is completely covered by the DISCUSSION 40-Gy isodose line with the filter installed. Better beam penetration is achieved at the brain centerline and the spar- As the dose escalation trials associated with BNCT re- ing effect of dose build-up is more pronounced with the 6Li search progress, more sophisticated treatments plans have filtered beam configuration. Quantifying the relative effec- been developed, changing from either single-field or paral- tiveness of the lithium filter depends on the mode of the lel opposed irradiations to multiple noncoplanar fields that dose prescription. When the maximum normal brain doses are arranged to maximize the dose delivered to the target are matched for the different beam configurations, the 6Li volume. A new 6Li filter has been designed, constructed, filtered beam provides a minimum tumor dose (biologically and installed in the MIT fission converter-based epithermal weighted) at the midline on central axis that is 9.0% higher neutron beam. This improvement in the clinical beam than with the unfiltered beam. However, when the prescrip- should prove beneficial when tumor control and efficacy are tion is specified as the mean normal brain dose as was the studied more systematically using delivery agents that can case during the last phase I trial (6), the 6Li-filtered beam selectively accumulate boron more uniformly in all tumor appears comparatively less advantageous with the minimum cells. tumor dose (biologically weighted) increasing by only 3.7% Treatment planning calculations of clinical cases that
  7. 7. 1490 I. J. Radiation Oncology ● Biology ● Physics Volume 67, Number 5, 2007 100 100 a b Shallow 80 80 Tumor Deep Volume (%) Volume (%) Brain Tumor Brain Tumor 60 60 40 40 20 20 0 0 0 20 40 60 0 20 40 60 Dose (Gyw) Dose (Gyw) Open Beam Li Filter Rx: Brain Mean Li Filter Rx: Brain Max Fig. 7. Dose–volume histograms for the normal brain and tumor for plans using open or 6Li filtered epithermal neutron beams for two different treatments: (a) patient with a deep right temporo-occipital tumor (mean biologically weighted brain dose 7.6 Gy) whose plan is shown in Figure 6; and (b) patient with multifocal disease having both shallow occipital and deep thalamic lesions (mean biologically weighted brain dose 7.0 Gy). Plans were computed for the 6Li filtered beams with two different dose prescriptions (i.e., the same mean brain dose and the same maximum normal brain dose as the open beam plan) for each patient. The doses assume a uniform distribution of boron and are biologically weighted (denoted by Gyw in the figure for emphasis). The 6Li filtration improves dose coverage of deep tumors but can significantly reduce doses for shallow sites. assume homogeneous uptake of boron throughout tumor 3 cm as determined from the point of intersection for the and normal tissue but at different concentrations show the filtered and unfiltered depth dose profiles in Fig. 5) provides potential benefit of including the 6Li filter in the epithermal no obvious benefit because of the reduced beam intensity, neutron beam when irradiating deep-seated tumors. The the decreased therapeutic ratio, and the poorer DVHs ob- minimum dose to tumor can be increased by 4% to 9% for tained for tumor. This highlights the need for a 6Li filter that the same mean biologically weighted dose to normal brain is readily removable from the beam line for optimum dose depending on how the dose is prescribed, i.e., using the delivery. mean or maximum brain dose. Irrespective of the mode of The 8-mm filter thickness was optimized to provide en- prescription, however, the increased tumor dose achieved hanced penetration of the thermal neutron distribution in- when using the filter while maintaining the same normal side the head. The design premise was to produce a beam tissue dose must be considered in the context of the dose– with the highest possible AD while also maximizing the response curves for tumor control probability (TCP) and ADDR and AR. This was achieved through tailoring the normal tissue complications that are usually steep and sim- incident energy spectrum by preferentially removing neu- ilar in shape. In particular the increase in beam penetration trons of the lowest energies in the epithermal range to provided by the additional filtration should initially help to improve the therapeutic characteristics of the beam. Mea- broaden the therapeutic window that BNCT trials are seek- surements inside an ellipsoidal water phantom confirmed ing to determine and thereafter provide added flexibility the accuracy of the Monte Carlo calculations of the beam when trying to optimize dose delivery to the target volume line and provided beam data essential for performing treat- that may well extend to the midline of the head. As an ment planning. Predicted gains in beam performance were example, Laramore et al. (30) have predicted a TCP for realized by an increase in the AD to 9.9 cm for the 12-cm- high-grade glioma using BNCT and epithermal neutron diameter field aperture with a concomitant loss in beam irradiations based on clinical responses to fast neutrons that intensity of 52%. Although the gains in penetration shows a narrow dose (biologically weighted) interval of achieved with the 6Li filter are comparable to those that can only 5 Gy between 30 and 35 Gy for little and complete be realized by increasing field size or beam collimation (13), tumor control probability respectively. An increase in tumor using the filter will provide a more homogeneous distribu- dose of 9% in this interval, as can be achieved using the 6Li tion of thermal neutrons and thus dose at depth in both filter, could produce a large increase in the predicted TCP tumor and normal brain. Although spectral shaping is costly (up to approximately 70%) without increasing the incidence in beam intensity, this is feasible for high intensity reactor of side effects. This would be highly desirable. Using the sources such as the FCB where treatment times for a single filter when irradiating tumor sites at shallower depths (i.e., irradiation to reach a maximum normal tissue dose of 12.5
  8. 8. Improved dose targeting for BNCT using 6Li filtration ● P. J. BINNS et al. 1491 Gy can still be achieved in less than 23 min. Furthermore depending on clinical need. The filter is interlocked to the loss of beam intensity will be made up at the MITR-II by automated dose control system that requires confirmation reloading the converter with fresh fuel and planned power of installation when setting the prescribed monitor units increases of the reactor. for treatment. This has been fully tested and, together The newly designed filter drawer required only minor with the completion of treatment planning calculations, is modifications to the existing beam line that allows easy now commissioned for routine use in the next series of installation of the filter disk, and inclusion is optional clinical trials. REFERENCES 1. Riley KJ, Binns PJ, Harling OK. A state-of-the-art epithermal MD: International Commission on Radiation Units and neutron irradiation facility for neutron capture therapy. Phys Measurements; 2000. Med Biol 2004;49:3725–3735. 17. Goorley JT, Kiger WS III, Zamenhof RG. Reference dosim- 2. Solaway AH, Tjarks W, Barnum DA, et al. The chemistry of etry calculations for neutron capture therapy with comparison neutron capture therapy. Chem Rev 1998;98:1515–1562. of analytical and voxel models. Med Phys 2002;29:145–156. 3. Harling OK, Riley KJ, Newton TH, et al. The fission con- 18. Harling OK, Roberts KA, Moulin DJ., et al. Head phantoms verter-based epithermal neutron irradiation facility at the Mas- for neutron capture therapy. Med Phys 1995;22:579 –583. sachusetts Institute of Technology Reactor. Nucl Sci Eng 19. Binns PJ, Riley KJ, Harling OK. Dosimetric measurements 2002;140:223–240. with a brain equivalent plastic walled ionization chamber in an 4. Riley KJ, Binns PJ, Harling OK. Performance characteristics epithermal neutron beam. Radiat Prot Dosim 2004;110:687– of the MIT fission converter based epithermal neutron beam. 692. Phys Med Biol 2003;48:943–958. 20. Rogus RD, Harling OK, Yanch JC. Mixed field dosimetry of 5. Palmer MR, Goorley JT, Kiger WS III, et al. Treatment neutron beams for boron neutron capture therapy at the planning and dosimetry for the Harvard-MIT phase I clinical MITR-II research reactor. Med Phys 1994;21:1611–1625. trial of cranial neutron capture therapy. Int J Radiat Oncol 21. ASTM (American Society for Testing and Materials). Biol Phys 2002;53:1361–1379. E262-97 Standard test method for determining thermal neu- 6. Kiger III WS, Lu XQ, Harling OK, et al. Preliminary treat- tron reaction and fluence rates by radioactivation techniques. ment planning and dosimetry for a clinical trial of neutron West Conshohocken, PA: ASTM; 1998. capture therapy using a fission converter epithermal neutron 22. Kiger WS III, Palmer MR, Riley KJ, et al. A pharmacokinetic beam. Appl Radiat Isot 2004;61:1075–1081. model for the concentration of 10B in blood after boronphe- 7. Capala J, Stenstam BH, Skold K, et al. Boron neutron capture nylalanine-fructose administration in humans. Radiat Res therapy for glioblastoma multiforme: Clinical studies in Swe- 2001;155:611– 618. den. J Neuro-Oncol 2003;62:135–144. 23. Coderre JA, Makar MS, Micca PL, et al. Derivations of 8. Binns PJ, Riley KJ, Harling OK. Epithermal neutron beams relative biological effectiveness for the high-LET radiations produced during boron neutron capture irradiations of the 9L for clinical studies of boron neutron capture therapy: A dosi- rat gliosarcoma in-vitro and in-vivo. Int J Radiat Oncol Biol metric comparison of seven beams. Radiat Res 2005;164:212– Phys 1993;27:1121–1129. 220. 24. Coderre JA, Morris GM. The radiation biology of boron 9. Gao W. Lithium filter for a fission converter-based boron neutron capture therapy. Radiat Res 1999;151:1–18. neutron capture therapy facility beam. Cambridge, MA: Mas- 25. Clement SD, Choi JR, Zamenhof RG, et al. Monte Carlo sachusetts Institute of Technology, 2005. MS Thesis. methods of neutron beam design for neutron capture therapy at 10. Yanch JC, Harling OK. Dosimetric effects of beam size and the MIT research reactor (MITR-II). In: Harling OK, Bernard collimation of epithermal neutrons for boron neutron capture JA, Zamenhof RG, editors. Neutron beam design, develop- therapy. Radiat Res 1993;135:131–145. ment, and performance for neutron-capture therapy. New 11. Bisceglie E, Colangelo P, Colonna N, et al. On the optimal York: Plenum Press; 1990. p 51– 69. energy of epithermal neutron beams for BNCT. Phys Med Biol 26. X-5 Monte Carlo Team. MCNP—A general Monte Carlo 2000;45:49 –58. N-particle transport code, version 5. Report no. LA-UR-03- 12. Kiger WS III, Sakamoto S, Harling OK. Neutronic design of 1987. Los Alamos National Laboratory, 2005. a fission converter-based epithermal neutron beam for neutron 27. Goorley JT. MCNP5 tally enhancements for lattices. Report capture therapy. Nucl Sci Eng 1999;131:1–22. no. LA-UR-04-3400. Los Alamos National Laboratory, 2004. 13. Sakamoto S, Kiger WS III, Harling OK. Sensitivity studies of 28. Kiger WS III, Albritton JR, Hochberg AG, et al. Performance beam directionality, beam size, and neutron spectrum for a enhancements of MCNP4B, MCNP5, and MCNPX for Monte fission converter-based epithermal neutron beam for boron Carlo radiotherapy planning calculations in lattice geometries. neutron capture therapy. Med Phys 1999;26:1979 –1988. Report no. LA-UR-04-4751. Los Alamos National Labora- 14. Briesmeister JF. MCNP—A General Monte Carlo N-Particle tory, 2004. Transport Code Version 4A. Los Alamos, CA: University of 29. ICRU. Photon, electron, proton and neutron interaction data California; 1993. for body tissues ICRU Report 46. Bethesda, MD: International 15. Kiger WS III, Santa Cruz GA, Gonzalez SJ, et al. Verification Commission on Radiation Units and Measurements; 1992. and validation of the NCT treatment planning program. In: 30. Laramore GE, Wheeler FJ, Wessol DE, et al. A tumor control Sauerwein W, Moss R, Wittig A, editors. Research and de- curve for malignant gliomas derived from fast neutron radio- velopment in neutron capture therapy. Bologna, Italy: Mon- therapy data: Implications for treatment delivery and com- duzzi Editore; 2002. p. 613– 616. pound selection. In: Larsson B, Crawford J, Weinreich R, 16. ICRU. Nuclear data for neutron and proton radiotherapy editors. Advances in neutron capture therapy. Amsterdam: and for radiation protection ICRU Report 63. Bethesda, Elsevier Science; 1997. p 580 –587.