Improvement of depth dose distribution using multiple-field irradiation in boron neutron capture therapy.

It is important that improvements are made to depth dose distribution in boron neutron capture therapy, because the neutrons do not reach the innermost regions of the human body. Here, we evaluated the dose distribution obtained using multiple-field irradiation in simulation. From a dose volume histogram analysis, it was found that the mean and minimum tumor doses were increased using two-field irradiation, because of improved dose distribution for deeper-sited tumors.

Dose estimation for internal organs during boron neutron capture therapy for body-trunk tumors.

Radiation doses during boron neutron capture therapy for body-trunk tumors were estimated for various internal organs, using data from patients treated at Kyoto University Research Reactor Institute. Dose-volume histograms were constructed for tissues of the lung, liver, kidney, pancreas, and bowel. For pleural mesothelioma, the target total dose to the normal lung tissues on the diseased side is 5Gy-Eq in average for the whole lung. It was confirmed that the dose to the liver should be carefully considered in cases of right lung disease.

Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography.

It is important to measure the microdistribution of (10)B in a cell to predict the cell-killing effect of new boron compounds in the field of boron neutron capture therapy. Alpha autoradiography has generally been used to detect the microdistribution of (10)B in a cell. Although it has been performed using a reactor-based neutron source, the realization of an accelerator-based thermal neutron irradiation field is anticipated because of its easy installation at any location and stable operation. Therefore, we propose a method using a cyclotron-based epithermal neutron source in combination with a water phantom to produce a thermal neutron irradiation field for alpha autoradiography. This system can supply a uniform thermal neutron field with an intensity of 1.7×10(9) (cm(-2)s(-1)) and an area of 40mm in diameter. In this paper, we give an overview of our proposed system and describe a demonstration test using a mouse liver sample injected with 500mg/kg of boronophenyl-alanine.

Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction.

OBJECTIVES: To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR). METHODS: EL4 tumour-bearing C57BL/J mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with γ-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a (10)B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. RESULTS: Following γ-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a (10)B-carrier, especially L-para-boronophenylalanine-(10)B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells. CONCLUSION: The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the (10)B-carrier used in the BNCR. ADVANCES IN KNOWLEDGE: The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control.

Effects of employing a ¹°B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy.

OBJECTIVES: To evaluate the effects of employing a (10)B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy (BNCT) by measuring the response of intratumour quiescent (Q) cells. METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumours received reactor thermal neutron beam irradiation following the administration of a (10)B-carrier [L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (BSH)] in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. RESULTS: BPA-BNCT increased the sensitivity of the total tumour cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a (10)B-carrier, MTH enhanced the sensitivity of the Q cell population. Without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with nicotinamide treatment, showed the potential to reduce the number of metastases more than BSH-BNCT. CONCLUSION: BSH-BNCT in combination with MTH improves local tumour control, while BPA-BNCT in combination with nicotinamide may reduce the number of lung metastases.

Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential.

OBJECTIVES: The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. RESULTS: 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. CONCLUSION: Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide.

A phantom experiment for the evaluation of whole body exposure during BNCT using cyclotron-based epithermal neutron source (C-BENS).

At Kyoto University Research Reactor Institute (KURRI), cyclotron-based epithermal neutron source was installed in December 2008, and the supplementary construction works have been performed. As of December 2010, the various irradiation characteristics important for BNCT were mostly evaluated. The whole body exposure during BNCT medical irradiation is one of the important characteristics. In this article, measurements of absorbed dose for thermal and fast neutrons and gamma-ray at ten positions corresponding to important organs are reported.

Experimental verification of beam characteristics for cyclotron-based epithermal neutron source (C-BENS).

A cyclotron-based epithermal neutron source has been developed for boron neutron capture therapy. This system consists of a cyclotron accelerator producing 1.1-mA proton beams with an energy of 30 MeV, a beam transport system coupled with a beryllium neutron production target, and a beam-shaping assembly (BSA) with a neutron collimator. In our previous work, the BSA was optimized to obtain sufficient epithermal neutron fluxes of ~10(9) cm(-2) s(-1) using a Monte Carlo simulation code. In order to validate the simulation results, irradiation tests using multi-foil activation at the surface of a gamma-ray shield located behind the collimator and water phantom experiments using a collimated epithermal neutron beam were performed. It was confirmed experimentally that the intensity of the epithermal neutrons was 1.2×10(9) cm(-2) s(-1).

Study on optimization of multiionization-chamber system for BNCT.

In order to monitor stability of doses from the four components such as thermal, epi-thermal, fast neutron and gamma-ray during BNCT irradiation, we are developing a multiionization-chamber system. This system is consisted of four kinds of ionization chamber, which have specific sensitivity for each component, respectively. Since a suitable structure for each chamber depends on the energy spectrum of the irradiation field, the optimization study of the chamber structures for the epi-thermal neutron beam of cyclotron-based epi-thermal neutron source (C-BENS) was performed by using a Monte Carlo simulation code "PHITS" and suitable chamber-structures were determined.

Evaluation for activities of component of Cyclotron-Based Epithermal Neutron Source (C-BENS) and the surface of concrete wall in irradiation room.

The workers employed in BNCT must enter the irradiation room just after an irradiation under the condition of remaining activities. To reduce the radiation exposure for the workers, it is important to identify the origins of the activities. In this research, the activities induced on the concrete wall surface were evaluated using MCNP-5 and the measurement results of thermal neutron distribution. Furthermore, the radioisotopes produced in the moderator were identified with a High Purity Germanium detector. It was found that the activities of the wall were mainly caused by (46)Sc, (60)Co and (152)Eu, and that (24)Na and (56)Mn were mainly produced in the moderator.

The optimization study of Bonner sphere in the epi-thermal neutron irradiation field for BNCT.

The optimization study on the Bonner sphere in the epi-thermal neutron irradiation field for BNCT was done for the moderator material, moderator size, and activation foils as a neutron detector in the sphere. The saturated activity for the activation foil was obtained from the calculated response, and the effective energy range for each Bonner sphere was determined from the saturated activity. We can see that boric acid solution moderator is suitable for the spectrum measurement of a epi-thermal neutron irradiation field.

Significance of manipulating tumour hypoxia and radiation dose rate in terms of local tumour response and lung metastatic potential, referring to the response of quiescent cell populations.

The purpose of this study was to evaluate the influence of manipulating intratumour oxygenation status and radiation dose rate on local tumour response and lung metastases following radiotherapy, referring to the response of quiescent cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-ray irradiation at high dose rate (HDR) or reduced dose rate (RDR) following treatment with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (proliferating + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Following HDR irradiation, nicotinamide and MTH enhanced the sensitivity of the total and Q-cell populations, respectively. The decrease in sensitivity at RDR irradiation compared with HDR irradiation was slightly inhibited by MTH, especially in Q cells. Without gamma-ray irradiation, nicotinamide treatment tended to reduce the number of lung metastases. With gamma-rays, in combination with nicotinamide or MTH, especially the former, HDR irradiation decreased the number of metastases more remarkably than RDR irradiation. Manipulating both tumour hypoxia and irradiation dose rate have the potential to influence lung metastasis. The combination with the acute hypoxia-releasing agent nicotinamide may be more promising in HDR than RDR irradiation in terms of reducing the number of lung metastases.

A feasibility study of the post-irradiation dose estimation with SPECT technique for BNCT.

Various radioactive nuclei are generated in and around the target volume after the irradiation for boron neutron capture therapy. By measuring and estimating the distributions of these nuclei with the technique of single photon emission computed tomography (SPECT), more accurate post-irradiation dose-estimation can be expected. The feasibility study was performed mainly by simulation. The radioactivity densities for Cl-38, Ca-49 and Na-24 just after the irradiation were calculated to be 100-1000 Bq/cm(3) in and around the target volume. It was confirmed that these nuclei could be detected by SPECT under some conditions. Using the density differences for these generated nuclei, discrimination between soft-tissue area and bone area can be achieved. In focusing on the shallower 1cm(3) voxel, the necessary counting-time for Na-24 was estimated to be a few tens of minutes when the distance between the SPECT detector and the voxel was shortened to 6 cm.

Improvement of dose distribution in phantom by using epithermal neutron source based on the Be(p,n) reaction using a 30 MeV proton cyclotron accelerator.

In order to generate epithermal neutrons for boron neutron capture therapy (BNCT), we proposed the method of filtering and moderating fast neutrons, which are emitted from the reaction between a beryllium target and 30 MeV protons accelerated by a cyclotron, using an optimum moderator system composed of iron, lead, aluminum, calcium fluoride, and enriched (6)LiF ceramic filter. At present, the epithermal-neutron source is under construction since June 2008 at Kyoto University Research Reactor Institute. This system consists of a cyclotron to supply a proton beam of about 1 mA at 30 MeV, a beam transport system, a beam scanner system for heat reduction on the beryllium target, a target cooling system, a beam shaping assembly, and an irradiation bed for patients. In this article, an overview of the cyclotron-based neutron source (CBNS) and the properties of the treatment neutron beam optimized by using the MCNPX Monte Carlo code are presented. The distribution of the RBE (relative biological effectiveness) dose in a phantom shows that, assuming a (10)B concentration of 13 ppm for normal tissue, this beam could be employed to treat a patient with an irradiation time less than 30 min and a dose less than 12.5 Gy-eq to normal tissue. The CBNS might be an alternative to the reactor-based neutron sources for BNCT treatments.

Boron neutron capture therapy for recurrent oral cancer and metastasis of cervical lymph node.

We treated 6 patients with recurrent oral cancer and metastasis to the cervical lymph nodes after conventional treatments in 5 and non-conventional in 1 using BNCT, and herein report our results. The clinical response in our patients ranged from CR to PD. In 5 cases, spontaneous pain decreased immediately after BNCT. Three of the 6 are alive at the time of writing and we found that BNCT contributed to QOL improvement in all.

Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer.

The effect of boron neutron capture therapy (BNCT) is correlated with the density of boron in the tumour. BNCT using intra-arterial administration of boron compounds was performed for recurrent head and neck cancer. Of the five patients treated, one achieved a complete response and four achieved a partial response. There was one case of transient headache but no severe adverse effects were observed. The advantages of using an intra-arterial administration route for BNCT, which causes the selective killing of tumour cells, might offer a new option in the treatment of recurrent head and neck malignancies. These promising results require further verification and optimization of the BNCT schedule; however, dose escalation would appear to be justified because the toxicity appears to be very low.

The usefulness of a continuous administration of tirapazamine combined with reduced dose-rate irradiation using {gamma}-rays or reactor thermal neutrons.

We clarified the usefulness of the continuous administration of tirapazamine (TPZ) in combination with reduced dose-rate irradiation (RDRI) using gamma-rays or reactor thermal neutrons. Squamous cell carcinoma (SCC) VII tumour-bearing mice received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. Then, they received a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ in combination with conventional dose-rate irradiation (CDRI) or RDRI using gamma-rays or thermal neutrons. After irradiation, the tumour cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labelling ( = quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total tumour cells was determined using tumours that were not pre-treated with BrdU. The sensitivity of both total and Q cells, especially of Q cells, was significantly reduced with RDRI compared with CDRI. Combination of TPZ increased the sensitivity of both populations, with a slightly more remarkable increase in Q cells. Furthermore, the continuous administration of TPZ raised the sensitivity of both total and Q cell populations, especially the former, more markedly than the single administration, whether combined with CDRI or RDRI using gamma-rays or thermal neutrons. From the viewpoint of solid tumour control as a whole, including intratumour Q-cell control, the use of TPZ, especially when administered continuously, combined with RDRI, is useful for suppressing the reduction in the sensitivity of tumour cells caused by the decrease in irradiation dose rate in vivo.

Arrangement of high-energy neutron irradiation field and shielding experiment using 4 m concrete at KENS.

An irradiation field of high-energy neutrons produced in the forward direction from a thick tungsten target bombarded by 500 MeV protons was arranged at the KENS spallation neutron source facility. In this facility, shielding experiment was performed with an ordinary concrete shield of 4 m thickness assembled in the irradiation room, 2.5 m downstream from the target centre. Activation detectors of bismuth, aluminium, indium and gold were inserted into eight slots inside the shield and attenuations of neutron reaction rates were obtained by measurements of gamma-rays from the activation detectors. A MARS14 Monte Carlo simulation was also performed down to thermal energy, and comparisons between the calculations and measurements show agreements within a factor of 3. This neutron field is useful for studies of shielding, activation and radiation damage of materials for high-energy neutrons, and experimental data are useful to check the accuracies of the transmission and activation calculation codes.

The irradiation system and dose estimation joint-system for NCT wider application in Kyoto University.

The research for neutron capture therapy (NCT) at the Kyoto University Research Reactor (KUR) has been remarkably developing after December 2001. However, the most important subject is the preparations for the KUR provisional shutdown coming in March 2006. In this paper, our present concept and plan are reported about the novel irradiation system and dose estimation system for wider applications of NCT. For the irradiation field, the target nuclear reaction was selected to (7)Li(p,n)(7)Be and the neutron moderator was selected to heavy water. The minimum proton current was about 13 mA for epi-thermal neutron irradiation, and about 9 mA for mix-neutron irradiation. In thermal neutron irradiation, the proton current needed more than 18 mA for 2.5-MeV protons, but only 4 mA for 5.0-MeV protons. For the dose estimation system, we are aiming at the completion of the "dose estimation joint-system". The data from the on-line measurement systems such as beam monitors and gamma-ray telescopes are fed back to the results for the in-body dose estimation, and then the dose estimations for irradiation field and a living body are jointed. For the beam-monitor system, multi-chamber method was adopted. The surveys were performed for the wall materials and chamber gases.

The usefulness of 2-nitroimidazole-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.

We evaluated the usefulness of five new (10)B-compounds (TX-2016, TX-2017, TX-2018, TX-2041, and TX-2042) as (10)B-carriers in boron neutron capture therapy (BNCT). They are 2-nitroimidazole-sodium borocaptate-(10)B (BSH) conjugates, that is, hybrid compounds that have both hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles, and thermal neutron-sensitizing unit, BSH. (10)B distribution analyses in tumors and blood indicated that TX-2041 has the most favorable characteristics for localizing a sufficient amount of (10)B into tumors and keeping the (10)B concentration high during neutron beam irradiation. In addition, TX-2041 showed a significantly higher radio-sensitization effect with reactor thermal neutron beams than BSH on both total (=proliferating (P) + quiescent (Q)) and hypoxia-rich Q cell populations in solid tumors. Further, TX-2041 clearly demonstrated a radio-sensitization effect with gamma-rays on both cell populations, which could never be achieved by BSH. (10)B-carriers with a hypoxic tumor cell-sensitizing effect on tumors with gamma-rays as well as the potential to selectively localize and keep (10)B in tumors, such as TX-2041, are promising for use in actual BNCT.