The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.

A dosimetry intercomparison between the boron neutron capture therapy groups of the Massachusetts Institute of Technology (MIT) and the Comisión Nacional de Energía Atómica (CNEA), Argentina was performed to enable combined analyses of NCT patient data between the different centers. In-air and dose versus depth measurements in a rectangular water phantom were performed at the hyperthermal neutron beam facility of the RA-6 reactor, Bariloche. Calculated dose profiles from the CNEA treatment planning system NCTPlan that were calibrated against in-house measurements required normalizations of 1.0 (thermal neutrons), 1.13 (photons), and 0.74 (fast neutrons) to match the dosimetry of MIT.

Neutron imaging techniques are powerful tools that can be applied to a wide array of problems, like imaging of fuel cells, residual stress analysis and detection of flaws in materials. These modern applications are increasingly demanding of high performing imaging devices. Coded Source Imaging (CSI) is a method that consists of a source composed of a pattern of many point-like sources. A phase contrast neutron imaging system is under construction at the Nuclear Reactor Laboratory at MIT. In this paper we present an overview of CSI and a progress report on the experimental setup.

Normalisation of prescribed dose in boron neutron capture therapy (BNCT) is needed to facilitate combining clinical data from different centres in the world to help expedite development of the modality. The approach being pursued within the BNCT community is based upon improving precision in the measurement and specification of absorbed dose. Beam characterisations using a common method are complete as are comparative dosimetry measurements between clinical centres in Europe and the USA. Results from treatment planning systems at these centres have been compared with measurements performed by MIT, and the scale factors determined are being confirmed with independent tests using measurements in an ellipsoidal water phantom. Dose normalisations have successfully been completed and applied to retrospectively analyse treatment plans from Brookhaven National Laboratory (1994-99) so that reported doses are consistently expressed with the trials performed during 1994-2003 at Harvard-MIT. Dose response relationships for adverse events and other endpoints can now be more accurately established.

The possible role of vascular endothelial cell damage in the loss of intestinal crypt stem cells and the subsequent development of the gastrointestinal (GI) syndrome is addressed. Mice received whole-body epithermal neutron irradiation at a dose rate of 0.57 +/- 0.04 Gy x min(-1). An additional dose was selectively targeted to endothelial cells from the short-ranged (5-9 microm) particles released from neutron capture reactions in 10B confined to the blood by incorporation into liposomes 70-90 nm in diameter. Different liposome formulations produced 45 +/- 7 or 118 +/- 12 microg/g 10B in the blood at the time of neutron irradiation, which resulted in total absorbed dose rates in the endothelial cells of 1.08 +/- 0.09 or 1.90 +/- 0.16 Gy x min(-1), respectively. At 3.5 d after irradiation, the intestinal crypt microcolony assay showed that the 2- to 3-fold increased doses to the microvasculature, relative to the nonspecific whole-body neutron beam doses, caused no additional crypt stem cell loss beyond that produced by the neutron beam alone. The threshold dose for death from the GI syndrome after neutron-beam-only irradiation was 9.0 +/- 0.6 Gy. There were no deaths from the GI syndrome, despite calculated absorbed doses to endothelial cells as high as 27.7 Gy, in the groups that received neutron beam doses of <9.0 Gy with boronated liposomes in the blood. These data indicate that endothelial cell damage is not causative in the loss of intestinal crypt stem cells and the eventual development of the GI syndrome.

The RBE of the new MIT fission converter epithermal neutron capture therapy (NCT) beam has been determined using intestinal crypt regeneration in mice as the reference biological system. Female BALB/c mice were positioned separately at depths of 2.5 and 9.7 cm in a Lucite phantom where the measured total absorbed dose rates were 0.45 and 0.17 Gy/ min, respectively, and irradiated to the whole body with no boron present. The gamma-ray (low-LET) contributions to the total absorbed dose (low- + high-LET dose components) were 77% (2.5 cm) and 90% (9.7 cm), respectively. Control irradiations were performed with the same batch of animals using 6 MV photons at a dose rate of 0.83 Gy/min as the reference radiation. The data were consistent with there being a single RBE for each NCT beam relative to the reference 6 MV photon beam. Fitting the data according to the LQ model, the RBEs of the NCT beams were estimated as 1.50 +/- 0.04 and 1.03 +/- 0.03 at depths of 2.5 and 9.7 cm, respectively. An alternative parameterization of the LQ model considering the proportion of the high- and low-LET dose components yielded RBE values at a survival level corresponding to 20 crypts (16.7%) of 5.2 +/- 0.6 and 4.0 +/- 0.7 for the high-LET component (neutrons) at 2.5 and 9.7 cm, respectively. The two estimates are significantly different (P = 0.016). There was also some evidence to suggest that the shapes of the curves do differ somewhat for the different radiation sources. These discrepancies could be ascribed to differences in the mechanism of action, to dose-rate effects, or, more likely, to differential sampling of a more complex dose-response relationship.

The aims of the present study were twofold: first, to evaluate the biodistribution of the carboranyl porphyrin H2TCP following intracerebral (i.c.) administration by means of convection enhanced delivery (CED) to rats bearing cerebral implants of the F98 glioma, and second to evaluate the efficacy of H2TCP as a boron delivery agent for BNCT. This was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor 48h after CED of 200 mu l of either 0.5 mg of H2TCP or a control, non-boronated porphyrin, H2TSSP. Untreated control rats all died within 28 days after tumor implantation and had a mean survival time (MST) of 25 +/- 2 days and irradiated controls, which received H2TSPP, had a MST of 29 +/- 3 days. Animals that received H2TCP by CED, followed by BNCT, had a MST of 34:0 days. Further studies are planned to evaluate the therapeutic efficacy of H2TCP and other boronated porphyrins as delivery agents for BNCT.

The purpose of the present study was to evaluate the efficacy of boron neutron capture therapy (BNCT) following convection enhanced delivery (CED) of either boronated epidermal growth factor (B-EGF) or the boronated monoclonal antibody (MoAb) cetuximab (B-C225) in rats bearing F98(EGFR) gliomas. Twenty-four hours following CED of I-125-labeled B-EGF or B-C225, 47.4% of the injected dose (ID) of B-EGF and 53.3% of the ID of B-C225 were retained in F98(EGFR) gliomas compared to 12.3-14.7% in F98 wildtype (1798(WT)), receptor negative tumors. Based on the favorable tumor uptake of the bioconjugate, BNCT studies were initiated at the Massachusetts Institute of Technology nuclear reactor (MITRII). The mean survival time (MST) of rats that received either B-EGF or B-C225 alone were 54 +/- 15 d and 55 +/- 15d, respectively, and in combination with i.v. boronophenylalanine (BPA), these were increased to 69 +/- 38 d and 64 +/- 19 d, respectively, compared to 40 +/- 5 d for BPA alone and 31 4 d for irradiated controls. Our data demonstrate the therapeutic efficacy of EGFR targeting boronated bioconjugates for BNCT of receptor positive gliomas.

A comparison of seven epithermal neutron beams used in clinical studies of boron neutron capture therapy (BNCT) in Sweden (Studsvik), Finland (Espoo), Czech Republic (ReZ), The Netherlands (Petten) and the U.S. (Brookhaven and Cambridge) was performed to facilitate sharing of preclinical and clinical results. The physical performance of each beam was measured using a common dosimetry method under conditions pertinent to brain irradiations. Neutron fluence and absorbed dose measurements were performed with activation foils and paired ionization chambers on the central axis both in air and in an ellipsoidal water phantom. The overall quality of each beam was assessed by figures of merit determined from the total weighted dose profiles that assumed the presence of boron in tissue. The in-air specific beam contamination from both fast neutrons and gamma rays ranged between 8 and 65 x 10(-11) cGy(w) cm2 for the different beams and the epithermal neutron flux intensities available at the patient position differed by more than a factor of 20 from 0.2-4.3 x 10(9) n cm(-2) s(-1). Percentage depth dose profiles measured in-phantom for the individual photon, thermal and fast-neutron dose components differed only subtly in shape between facilities. Assuming uptake characteristics consistent with the currently used boronated phenylalanine, all the epithermal beams exhibit a useful penetration of 8 cm or greater that is sufficient to irradiate a lesion seated at the brain midline. The performance of the existing facilities will benefit from the introduction of advanced compounds through improved beam penetrability. This could increase by as much as 2 cm for the purest of beams, although the beam intensities generally need to be increased to between 2-5 x 10(9) n cm(-2) s(-1) to maintain manageable irradiation times. These data provide the first consistent measurement of beam performance at the different centers and will enable a preliminary normalization of the calculated patient dosimetry.

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. (c) 2005 by Radiation Research Society.

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

At the Massachusetts Institute of Technology (MIT) the first fission converter-based epithermal neutron beam (FCB) has proven suitable for use in clinical trials of boron neutron capture therapy (BNCT). The modern facility provides a high intensity beam together with low levels of contamination that is ideally suited for use with future, more selective boron delivery agents. Prescriptions for normal tissue tolerance doses consist of 2 or 3 fields lasting less than 10 min each with the currently available beam intensity, that are administered with an automated beam monitoring and control system to help ensure safety of the patient and staff alike. A quality assurance program ensures proper functioning of all instrumentation and safety interlocks as well as constancy of beam output relative to routine calibrations. Beam line shutters and the medical room walls provide sufficient shielding to enable access and use of the facility without affecting other experiments or normal operation of the multipurpose research reactor at MIT. Medical expertise and a large population in the greater Boston area are situated conveniently close to the university, which operates the research reactor 24 h a day for approximately 300 days per year. The operational characteristics of the facility closely match those established for conventional radiotherapy, which together with a near optimum beam performance ensure that the FCB is capable of determining whether the radiobiological promise of NCT can be realized in routine practice.

A patient collimator for the fission converter based epithermal neutron beam (FCB) at the Massachusetts Institute of Technology Research Reactor (MITR-II) was built for clinical trials of boron neutron capture therapy (BNCT). A design was optimized by Monte Carlo simulations of the entire beam line and incorporates a modular construction for easy modifications in the future. The device was formed in-house by casting a mixture of lead spheres (7.6 mm diameter) in epoxy resin loaded with either 140 mg cm−3 of boron carbide or 210 mg cm−3 of lithium fluoride (95% enriched in 6Li). The cone shaped collimator allows easy field placement anywhere on the patient and is equipped with a laser indicator of central axis, beam's eye view optics and circular apertures of 80, 100, 120 and 160 mm diameter. Beam profiles and the collateral dose in a half-body phantom were measured for the 160 mm field using fission counters, activation foils as well as tissue equivalent (A-150) and graphite walled ionization chambers. Leakage radiation through the collimator contributes less than 10% to the total collateral dose up to 0.15 m beyond the edge of the aperture and becomes relatively more prominent with lateral displacement. The measured whole body dose equivalent of 24 ± 2 mSv per Gy of therapeutic dose is comparable to doses received during conventional therapy and is due principally (60–80%) to thermal neutron capture reactions with boron. These findings, together with the dose distributions for the primary beam, demonstrate the suitability of this patient collimator for BNCT.

Cetuximab (IMC-C225) is a monoclonal antibody directed against both the wild-type and mutant vIII isoform of the epidermal growth factor receptor (EGFR). The purpose of the present study was to evaluate the monoclonal antibody (MoAb), cetuximab, as a boron delivery agent for neutron capture therapy (NCT) of brain tumors. Twenty-four hours following intratumoral (i.t.) administration of boronated cetuximab (C225-G5-B1100), the mean boron concentration in rats bearing either F98EGFR or F98WT gliomas were 92.3±23.3μg/g and 36.5±18.8μg/g, respectively. In contrast, the uptake of boronated dendrimer (G5-B1000) was 6.7±3.6μg/g. Based on its favorable in vivo uptake, C225-G5-B1100 was evaluated as a delivery agent for BNCT in F98EGFR glioma bearing rats. The mean survival time (MST) of rats that received C225-G5-B1100, administered by convection enhanced delivery (CED), was 45±3d compared to 25±3d for untreated control animals. A further enhancement in MST to >59d was obtained by administering C225-G5-B1100 in combination with i.v. boronophenylalanine (BPA). These data are the first to demonstrate the efficacy of a boronated MoAb for BNCT of an intracerebral (i.c.) glioma and are paradigmatic for future studies using a combination of boronated MoAbs and low molecular weight delivery agents.

The tissue substitute A-181 plastic, which has an elemental composition matching both the constituent hydrogen and nitrogen of brain tissue, was assessed for dosimetry in boron neutron capture therapy (BNCT). The sensitivity of an A-181 walled ionization chamber relative to photons for all neutrons in a clinical epithermal beam was calculated to vary between 0.79 +/- 0.04 in-air and 0.95 +/- 0.01 at depths of 4 cm and greater in-phantom. Differences in the total neutron doses measured with A-150 and A-181 plastic-walled chambers were attributed, within experimental error, to the dose produced by thermal neutron capture reactions from the different concentrations of nitrogen in the two tissue substitutes. The response of the A-181 chamber was converted to total neutron dose with an uncertainty increasing with depth in-phantom from 13 to 23% the magnitude of which is determined by the subtraction of a relatively large photon dose. The use of A-181 in place of A-150 plastic will no longer require partitioning the measured neutron dose by energy and should simplify dose reporting in BNCT.

Data from the Harvard–MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm3) dose and average whole-brain dose show a steep dose–response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED50±SE) were 6.2±1.0Gy(w) for average whole-brain dose and 14.1±1.8Gy(w) for peak brain dose.

The international collaboration that was organized to undertake a dosimetry exchange for purposes of combining clinical data from different facilities conducting neutron capture therapy has continued since its founding at the 9th ISNCT symposium in October 2000. The thrust towards accumulating physical dosimetry data for comparison between different participants has broadened to include facilities in Japan and the determination of spectral descriptions of different beams. Retrospective analysis of patient data from the Brookhaven Medical Research Reactor is also being considered for incorporation into this study to increase the pool of available data. Meanwhile the next essential phase of comparing measurements of visiting dosimetry groups with treatment plan calculations from the host institutes has commenced. Host centers from Petten, Finland and the Czech Republic in Europe and MIT in the USA have applied the regular calculations and clinical calibrations from their current clinical studies, to generate treatment plans in the large standard phantom used for measurements by visiting participants. These data have been exchanged between the participants and scaling factors to relate the separate dose components between the different institutes are being determined. Preliminary normalization of measured and calculated dosimetry for patients is nearing completion to enable the physical radiation doses that comprise a treatment prescription at a host institute to be directly related to the corresponding measured doses of a visiting group. This should serve as an impetus for the direct comparison of patient data although the clinical requirements for achieving this need to be clearly defined. This may necessitate more extensive comparisons of treatment planning calculations through the solution of test problems and clarification regarding the question of dose specification from treatment calculations in general.

The whole lung of rats was irradiated with X-rays, thermal neutrons, or thermal neutrons in the presence of p-boronophenylalanine (BPA). A ⩾20% increase in breathing rate, in the period 40–80 days after irradiation, was indicative of radiation-induced pneumonitis. The ED50 (±SE) for a ⩾20% increase in breathing rate, relative to age-matched controls, was 11.6±0.13 Gy for X-rays and 9.6±0.08 Gy for neutrons only. This indicated a thermal neutron beam RBE of 1.2 and an RBE of 2.2 for the high-LET components of the dose, assuming a dose reduction factor of 1.0 for gamma rays. Preliminary data indicate the compound biological effectiveness factor for BPA in the lung is approximately 1.5.

The purpose of the present study was to further evaluate a boronated dendrimer (BD)-epidermal growth factor bioconjugate (BD-EGF), administered by means of convection enhanced delivery (CED), as a molecular targeting agent for boron neutron capture therapy (BNCT) of the F98EGFR glioma. Twenty-four hours following CED of 125I-labeled BD-EGF 47.4% of the injected dose (ID) was retained in F98EGFR gliomas compared to 12.3% in F98WT (wildtype) receptor negative tumors. Normal brain values were in the range of 5.9–10.1% ID in the tumor bearing cerebral hemisphere. Boron concentrations in F98EGFR gliomas were 22.3 and 11.7 μg/g following CED and i.t. injection, respectively. Based on these results, BNCT studies were initiated at the Massachusetts Institute of Technology nuclear reactor (MITRII). The mean survival time (MST) of rats that received BD-EGF either alone or in combination with boronophenylalanine (BPA), injected i.v., were 53±13 d and >61±14 d, respectively, compared to 40±5 d for BPA alone and 31±4 d for irradiated controls. These data show that CED improved the radiobiological effectiveness of BD-EGF and lay the groundwork for future studies using combinations of boron delivery agents for NCT of EGFR(+) gliomas.