Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy

Hatanaka, Hiroshi; Nakagawa, Yoshinobu

doi:10.1016/0360-3016(94)90479-0

Cited by 234 publications

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“…The peak of this thermalization of epithermal neutrons is about 3 cm in depth. The heavy water facility at Kyoto University Reactor (KUR) was remodeled in 1996 for production of an epithermal neutron beam.2) We expected that the aforesaid problem (poor penetration with a thermal neutron beam) might be overcome and it might become feasible to apply BNCT to malignant hepatic tumors.We examined the effects of BNCT on experimental liver tumors and normal hepatocytes by using two boron compounds which are being used in clinical BNCT trials for malignant glioma and malignant melanoma, [3][4][5] to explore the feasibility of BNCT treatment of liver tumors. …”

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The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

Suzuki

Masunaga

Kinashi

et al. 2000

Japanese Journal of Cancer Research

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To explore the feasibility of employing boron neutron capture therapy (BNCT) to treat liver tumors, the effects of BNCT were investigated by using liver tumor models and normal hepatocytes in mice. Liver tumor models in C3H mice were developed by intrasplenic injection of SCCVII tumor cells. After borocaptate sodium (BSH) and boronophenylalanine (BPA) administration, 10 B concentrations were measured in tumors and liver and the liver was irradiated with thermal neutrons. The effects of BNCT on the tumor and normal hepatocytes were studied by using colony formation assay and micronucleus assay, respectively. To compare the effects of BSH-BNCT and BPA-BNCT, the compound biological effectiveness (CBE) factor was determined. The CBE factors for BSH on the tumor were 4.22 and 2.29 using D 10 and D 0 as endpoints, respectively. Those for BPA were 9.94 and 5.64. In the case of hepatocytes, the CBE factors for BSH and BPA were 0.94 and 4.25, respectively. Tumor-to-liver ratios of boron concentration following BSH and BPA administration were 0.3 and 2.8, respectively. Considering the accumulation ratios of 10 B, the therapeutic gain factors for BSH and BPA were 0.7-1.3 and 3.8-6.6, respectively. Therefore, it may be feasible to treat liver tumors with BPA-BNCT. Key words: BNCT -BSH -BPA -Liver tumorsVarious therapeutic options have been examined for the treatment of unresectable primary and secondary malignant tumors in the liver. These include percutaneous ethanol injection, intraarterial drug infusion, embolization, intraarterial chemoembolization and radiotherapy. However, the results of these treatments have not been satisfactory. In many cases there are multiple tumors, and the liver cannot tolerate large treatment volumes, especially in radiotherapy. Boron neutron capture therapy (BNCT) which combines an administration of a tumor-seeking boron compound with thermal neutron irradiation might be an effective treatment for malignant hepatic tumors for the following reasons. In the boron neutron capture reaction, 10 B absorbs a thermal neutron and releases two high linear energy transfer (LET) particles, an α particle and a 7 Li nucleus. These particles have path lengths of 9 and 4 µm, respectively, depositing all their energy within a range of about one cell diameter from the capture reaction site. Accordingly these high-LET particles have large relative biological effectiveness (RBE), and effective cell killing can be expected in malignant tumors, which are resistant to conventional radiotherapy using photons or electrons. The path lengths of these particles are so short that if tumor cells accumulate the boron compound selectively, only tumor cells can be killed.A major limitation in the application of BNCT using thermal neutrons is the tumor depth. Deep-seated tumors, such as hepatic tumors, are difficult to treat because of the poor penetration of thermal neutrons, which have energies <0.5 eV and a 15-16 mm half-value layer in water. Epithermal beams, with energies 0.5 eV to 10 keV, have better penetration in tiss...

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“…We examined the effects of BNCT on experimental liver tumors and normal hepatocytes by using two boron compounds which are being used in clinical BNCT trials for malignant glioma and malignant melanoma, [3][4][5] to explore the feasibility of BNCT treatment of liver tumors. was prepared as follows.…”

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The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

Suzuki

Masunaga

Kinashi

et al. 2000

Japanese Journal of Cancer Research

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“…The microlocation and differential accumulation of 10 B will therefore have a critical bearing on the therapeutic outcome of BNCT, and also on the response of normal tissue in the irradiated volume. In the clinical situation, relatively high therapeutic ratios have been obtained enabling BNCT to be given as a single dose or a small number (maximum 4) of dose fractions (Hatanaka et al, 1994;Coderre et al, 1997).…”

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Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

et al. 2000

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Summary Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 ( 10 B) in the oral mucosa to the biological effectiveness of the 10 B(n,α) 7 Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10 B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10 B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10 B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10 B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10 B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10 B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10 B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10 B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiationinduced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10 B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT.

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“…Therefore, the combined targeting of neutron irradiation and boron accumulation can lead to selective damaging of tumor cells. Borocaptate sodium, Na 2 B 12 H 11 SH (BSH) was used as BNCT agent in Japanese patients since 1968 (3) and is now under evaluation in a European Phase I clinical trial (4).…”

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In vivo imaging of the neutron capture therapy agent BSH in mice using ¹⁰B MRI

Bendel

Koudinova

Salomon

2001

Magnetic Resonance in Med

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Boron neutron capture therapy (BNCT) is an experimental cancer treatment modality requiring the targeting of 10 B-enriched compounds to the tumor, which is then irradiated by low-energy neutrons. One of the boron-containing compounds used for this purpose is the mercaptoborane Na 2 B 12 H 11 SH (BSH). The first in vivo MR images of 10 B-enriched BSH are presented here. BSH, injected into the tail vein of mice with implanted M2R melanoma xenografts, was imaged using 3D gradient echo 10 B MRI. 10 B NMR spectroscopy, localized mainly to the tumor by virtue of the use of a small surface coil, was applied to measure the T 1 (2.9 ؎ 0. Boron neutron capture therapy (BNCT) is based on the high cross section of 10 B for capturing thermal neutrons (1,2). This nuclear reaction yields alpha particles and recoiling lithium nuclei, both with high linear energy transfer (LET) and relatively short spatial range (ϳ10 m). Therefore, the combined targeting of neutron irradiation and boron accumulation can lead to selective damaging of tumor cells. Borocaptate sodium, Na 2 B 12 H 11 SH (BSH) was used as BNCT agent in Japanese patients since 1968 (3) and is now under evaluation in a European Phase I clinical trial (4).The ability for noninvasive imaging of the administered drug is a highly desirable goal for both the research of BNCT and for its clinical implementation. So far, the in vivo MR imaging of BSH was demonstrated only for the natural abundance compound (5), using 11 B detection ( 11 B has 80% natural abundance). This approach is obviously not suitable for clinical applications, where the boronated molecules are enriched in 10 B to over 95%. It was always assumed that direct 10 B detection would not be sensitive enough for MRI of BNCT agents, due to the low gyromagnetic ratio of 10 B, and therefore considerable efforts were devoted to the development and implementation of indirect detection methods. In BSH, 11 out of the 12 boron nuclei are coupled to protons (J ϭ 43 Hz) and several reports exploiting this fact for 10 B-edited, proton detection of BSH were published (6 -9). We decided, nevertheless, to explore the possibility for direct 10 B MRI of BSH, following measurements indicating that indirect 1 H detection may not be as advantageous as previously assumed (10). MATERIALS AND METHODSMouse M2R melanoma cells, routinely maintained as monolayers, were scraped, suspended in saline at 1 ϫ 10 6 cells / 0.25 ml, and injected subcutaneously into the rear thigh of CD1 nude mice. Mice (n ϭ 3) with tumors grown to about 1-2 cm in size were used for MRI experiments and 10 B relaxation time measurements (7). A solution (180 l) containing 0.11 M of 10 B-enriched (Ͼ95%) BSH (Boron Biologicals, Raleigh, NC) in PBS was injected into the mice tail veins. During the injection and the subsequent NMR experiments, the mice were anesthetized with Isoflurane (Medeva, Bethlehem, PA) in 70% N 2 O/30% O 2 . NMR experiments were conducted on a spectrometer with a 4.7T horizontal 30 cm bore magnet (Biospec, Bruker, Ettlingen, Germany). For MRI, ...

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Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy

Cited by 234 publications

References 6 publications

The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

In vivo imaging of the neutron capture therapy agent BSH in mice using ¹⁰B MRI

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Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy

Cited by 234 publications

References 6 publications

The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

The Effects of Boron Neutron Capture Therapy on Liver Tumors and Normal Hepatocytes in Mice

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

In vivo imaging of the neutron capture therapy agent BSH in mice using 10B MRI

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In vivo imaging of the neutron capture therapy agent BSH in mice using ¹⁰B MRI