Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era.

Boron neutron capture therapy (BNCT) has a unique property of tumor-cell-selective heavy-particle irradiation. BNCT can form large dose gradients between cancer cells and normal cells, even if the two types of cells are mingled at the tumor margin. This property makes it possible for BNCT to be used for pre-irradiated locally recurrent tumors. Shallow-seated, locally recurrent lesions have been treated with BNCT because of the poor penetration of neutrons in the human body. BNCT has been used in clinical studies for recurrent malignant gliomas and head and neck cancers using neutron beams derived from research reactors, although further investigation is warranted because of the small number of patients. In the latter part of this review, the development of accelerator-based neutron sources is described. BNCT for common cancers will become available at medical institutes that are equipped with an accelerator-based BNCT system. Multiple metastatic lung tumors have been investigated as one of the new treatment candidates because BNCT can deliver curative doses of radiation to the tumors while sparing normal lung tissue. Further basic and clinical studies are needed to move toward an era of accelerator-based BNCT when more patients suffering from refractory cancers will be treated.

A Monte Carlo feasibility study for neutron based real-time range verification in proton therapy.

Uncertainties in the proton range in tissue during proton therapy limit the precision in treatment delivery. These uncertainties result in expanded treatment margins, thereby increasing radiation dose to healthy tissue. Real-time range verification techniques aim to reduce these uncertainties in order to take full advantage of the finite range of the primary protons. In this paper, we propose a novel concept for real-time range verification based on detection of secondary neutrons produced in nuclear interactions during proton therapy. The proposed detector concept is simple; consisting of a hydrogen-rich converter material followed by two charged particle tracking detectors, mimicking a proton recoil telescopic arrangement. Neutrons incident on the converter material are converted into protons through elastic and inelastic (n,p) interactions. The protons are subsequently detected in the tracking detectors. The information on the direction and position of these protons is then utilized in a new reconstruction algorithm to estimate the depth distribution of neutron production by the proton beam, which in turn is correlated with the primary proton range. In this paper, we present the results of a Monte Carlo feasibility study and show that the proposed concept could be used for real-time range verification with millimetric precision in proton therapy.

Accelerator driven neutron source design via beryllium target and 208Pb moderator for boron neutron capture therapy in alternative treatment strategy by Monte Carlo method.

AIMS: The reactor has increased its area of application into medicine especially boron neutron capture therapy (BNCT); however, accelerator-driven neutron sources can be used for therapy purposes. The present study aimed to discuss an alternative method in BNCT functions by a small cyclotron with low current protons based on Karaj cyclotron in Iran. MATERIALS AND METHODS: An epithermal neutron spectrum generator was simulated with 30 MeV proton energy for BNCT purposes. A low current of 300 µA of the proton beam in spallation target concept via 9Be target was accomplished to model neutron spectrum using 208Pb moderator around the target. The graphite reflector and dual layer collimator were planned to prevent and collimate the neutrons produced from proton interactions. Neutron yield per proton, energy distribution, flux, and dose components in the simulated head phantom were estimated by MCNPX code. RESULTS: The neutron beam quality was investigated by diverse filters thicknesses. The maximum epithermal flux transpired using Fluental, Fe, Li, and Bi filters with thicknesses of 7.4, 3, 0.5, and 4 cm, respectively; as well as the epithermal to thermal neutron flux ratio was 161. Results demonstrated that the induced neutrons from a low energy and low current proton may be effective in tumor therapy using 208Pb moderator with average lethargy and also graphite reflector with low absorption cross section to keep the generated neutrons. CONCLUSIONS: Combination of spallation-based BNCT and proton therapy can be especially effective, if a high beam intensity cyclotron becomes available.

[Ozone therapy for radiation reactions and skin lesions after neutron therapy in patients with malignant tumors].

The article discusses the problem of radiation complications from normal tissues in patients after therapy with fast neutrons of 6.3 MeV. The methods of treatment using ozone technologies in patients with radiation reactions and skin lesions on the areas of irradiation after neutron and neutron-photon therapy have been worked out. Ozone therapy showed its harmlessness and increased efficiency of complex treatment of these patients.

The alanine detector in BNCT dosimetry: dose response in thermal and epithermal neutron fields.

PURPOSE: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. METHODS: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a (60)Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model. RESULTS: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. CONCLUSIONS: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.

The safety and usefulness of neutron brachytherapy and external beam radiation in the treatment of patients with gastroesophageal junction adenocarcinoma with or without chemotherapy.

PURPOSE: To assess the safety and usefulness of neutron brachytherapy (NBT) as an adjuvant in the treatment of patients with gastroesophageal junction adenocarcinoma (GEJAC) with external beam radiation (EBRT), with or without chemotherapy. METHODS AND MATERIALS: In total, 197 patients with localized, advanced GEJAC received EBRT and NBT with or without chemotherapy. Radiotherapy consisted of external irradiation to a total dose of 40-54 Gy (median 50 Gy) and brachytherapy to 8-25 Gy (median 20 Gy) in two to five fractions. In total, 88 patients received chemotherapy that consisted of two cycles of a regimen with CDDP and 5FU from days l-4. The cycles were administered on days 1 and 29. MMC was given alone in bolus injection on day 1 each week. The cycles were administered on days 1, 8, 15 and 22. RESULTS: The duration of follow-up ranged from six to 106 months (median 30.4 months). The median survival time for the 197 patients was 13.3 months, and the one, two, three- and five-year rates for overall survival were 57.1%, 35.1%, 23.0% and 9.2%, respectively. For acute toxicity, no incidences of fistula and massive bleeding were observed during this treatment period. In total, 159 (80.7%) patients developed Grade 2 hematologic toxicity and 146 (74.1%) patients developed Grade ≥ 2 esophagitis. The median times of incidence of fistula and bleeding were 9.5 (3-27.3) months and 12.7 (5-43.4) months, respectively. The incidence of severe, late complications was related to higher NBT dose/f (20-25 Gy/5 F) and higher total dose(≥70 Gy). In total, 75.2% of the patients resumed normal swallowing and 2.0% had some residual dysphagia (non-malignant) requiring intermittent dilatation. CONCLUSION: A combination of EBRT and NBT with the balloon type applicator was feasible and well tolerated. Better local-regional control and overall survival cannot achieved by a higher dose, and in contrast, a higher dose caused more severe esophageal injury.

Boron neutron capture therapy (BNCT) for the treatment of spontaneous nasal planum squamous cell carcinoma in felines.

Recently, Boron neutron capture therapy (BNCT) was successfully applied to treat experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa, with no damage to normal tissue. It was also shown that treating spontaneous nasal planum SCC in terminal feline patients with low dose BNCT is safe and feasible. In an extension of this work, the present study aimed at evaluation of the response of tumor and dose-limiting normal tissues to potentially therapeutic BNCT doses. Biodistribution studies with (10)B-boronophenylalanine (BPA enriched in (10)B) as a (10)B carrier were performed on three felines that showed advanced nasal planum SCC without any standard therapeutic option. Following the biodistribution studies, BNCT mediated by (10)BPA was done using the thermalized epithermal neutron beam at the RA-6 Nuclear Reactor. Follow-up included clinical evaluation, assessment of macroscopic tumor and normal tissue response and biopsies for histopathological analysis. The treated animals did not show any apparent radiation-induced toxicity. All three animals exhibited partial tumor control and an improvement in clinical condition. Enhanced therapeutic efficacy was associated with a high (10)B content of the tumor and a small tumor size. BNCT is therefore believed to be potentially effective in the treatment of spontaneous SCC. However, improvement in targeting (10)B into all tumor cells and delivering a sufficient dose at a greater depth are still required for the treatment of deep-seated, large tumors. Future studies are needed to evaluate the potential efficacy of the dual mode cellular (e.g. BPA-BNCT) and vascular (e.g. GB-10-BNCT) targeting protocol in a preclinical scenario, employing combinations of (10)B compounds with different properties and complementary uptake mechanisms.

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.

The medical-irradiation characteristics for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

At the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor, the mix irradiation of thermal and epi-thermal neutrons, and the solo irradiation of epi-thermal neutrons are available additionally to the thermal neutron irradiation, and then the neutron capture therapy (NCT) at this facility became more flexible, after the update in 1996. The estimation of the depth dose distributions in NCT clinical irradiation, were performed for the standard irradiation modes of thermal, mixed and epi-thermal neutrons, from the both sides of experiment and calculation. On the assumption that the 10B concentration in tumor part was 40 ppm and the ratio of tumor to normal tissue was 3.5, the advantage depth were estimated to 5.4, 6.0, and 8.0, for the respective standard irradiation modes. It was confirmed that the various irradiation conditions can be selected according to the target-volume conditions, such as size, depth, etc. Besides, in the viewpoint of the radiation shielding for patient, it was confirmed that the whole-body exposure is effectively reduced by the new clinical collimators, compared with the old one.

Controllability of depth dose distribution for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

The updating construction of the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor has been performed from November 1995 to March 1996 mainly for the improvement in neutron capture therapy. On the performance, the neutron irradiation modes with the variable energy spectra from almost pure thermal to epi-thermal neutrons became available by the control of the heavy-water thickness in the spectrum shifter and by the open-and-close of the cadmium and boral thermal neutron filters. The depth distributions of thermal, epi-thermal and fast neutron fluxes were measured by activation method using gold and indium, and the depth distributions of gamma-ray absorbed dose rate were measured using thermo-luminescent dosimeter of beryllium oxide for the several irradiation modes. From these measured data, the controllability of the depth dose distribution using the spectrum shifter and the thermal neutron filters was confirmed.

Experimental verification of improved depth-dose distribution using hyper-thermal neutron incidence in neutron capture therapy.

We have proposed the utilization of 'hyper-thermal neutrons' for neutron capture therapy (NCT) from the viewpoint of the improvement in the dose distribution in a human body. In order to verify the improved depth-dose distribution due to hyper-thermal neutron incidence, two experiments were carried out using a test-type hyper-thermal neutron generator at a thermal neutron irradiation field in Kyoto University Reactor (KUR), which is actually utilized for NCT clinical irradiation. From the free-in-air experiment for the spectrum-shift characteristics, it was confirmed that the hyper-thermal neutrons of approximately 860 K at maximum could be obtained by the generator. From the phantom experiment, the improvement effect and the controllability for the depth-dose distribution were confirmed. For example, it was found that the relative neutron depth-dose distribution was about 1 cm improved with the 860 K hyper-thermal neutron incidence, compared to the normal thermal neutron incidence.

The Denekamp diadems--a review of Julie's achievements.

Dr Julie Denekamp, DSc, PhD, BSc was present at a symposium held in her honour in Uppsala in February 2001. This article presents some biographical details and summarizes the main features of the scientific work for which she is known in radiobiology applied to cancer treatment, now called Translational Research. Topics include fractionation, proliferation in normal tissues as well as tumours, early versus late reactions, radiosensitizers, vascular attack in tumours, neutrons (and pions), radiosensitizers, radioprotectors, hyperthermia, research methodology, and theoretical modelling.

Predictions of a stochastic model of bone marrow cell survival in high dose rate radiation fields with arbitrary neutron to gamma-ray absorbed dose rate ratios.

In this paper, a stochastic model of cell survival, which was developed by Cotlet and Blue, based on the work of Jones, is extended to describe bone marrow cell survival in high dose rate radiation fields with arbitrary neutron to gamma-ray absorbed dose rate ratios. Mathematical formulas are obtained that describe the interaction of the neutron and gamma-ray components of the absorbed dose, for radiation fields with arbitrary neutron to gamma-ray dose rate ratios, for exposures of cells to various absorbed doses, at various high dose rates.

Measurements and calculations of thermal neutron fluence rate and neutron energy spectra resulting from moderation of 252Cf fast neutrons: applications for neutron capture therapy.

252Cf is a neutron emitting radioisotope which has promise for both standard brachytherapy and neutron capture enhanced brachytherapy. In this study, experimental measurements and calculations were used to determine the thermal neutron fluence rate, phi(th) [n cm(-2) s(-1) mg(-1)], in the vicinity of 252Cf applicator tube (AT) type sources. Results of these measurements were confirmed with Monte Carlo calculations performed in a distributed manner on multiple workstations using MCNP. Three studies were executed: (1) relative phi(th) as a function of distance from a 252Cf AT source in an A-150 tissue equivalent plastic phantom using thermoluminescent dosimeters (TLDs) of varying 6Li/Li enrichment, (2) phi(th) measured with gold foils in a 114 liter water phantom 5 cm from two 252Cf AT sources, and (3) calculations of the impact of phantom material composition (e.g., A-150, water, brain, muscle) on phi(th) from moderated 252Cf fast neutrons. TLD results and Monte Carlo calculations in A-150 of relative phi(th) typically agreed within 1% and at most differed by 3% for distances from 1 to 6 cm. Foil measurements followed the ASTM E 262-86e protocol, and the ratio of activated plain and Cd encased gold foils (7.31) agreed well with the calculated ratio (7.26). Measured phi(th) at 5 cm (1.70+/-0.10 x 10(7) n cm(-2) s(-1) mg(-1)) was 10% greater than that determined using MCNP (1.55+/-0.12 x 10(7) n cm(-2) s(-1) mg(-1)), but was within the combined uncertainties. Compared with A-150 at a distance of 1 cm, phi(th) was 20%, 22%, and 32% less for water, brain, and muscle, respectively; these ratios decreased to 16%, 16%, and 24% less, respectively, at a distance of 5 cm from the source in a 15 cm diameter phantom. Comparisons of these results generally agreed with those in the literature for a value of 2 x 10(7) n cm(-2) s(-1) mg(-1) in water at 3 cm.

A consistent set of neutron kerma coefficients from thermal to 150 MeV for biologically important materials.

Neutron cross sections for nonelastic and elastic reactions on a range of elements have been evaluated for incident energies up to 150 MeV. These cross sections agree well with experimental cross section data for charged-particle production as well as neutron and photon production. Therefore they can be used to determine kerma coefficients for calculations of energy deposition by neutrons in matter. Methods used to evaluate the neutron cross sections above 20 MeV, using nuclear model calculations and experimental data, are described. Below 20 MeV, the evaluated cross sections from the ENDF/B-VI library are adopted. Comparisons are shown between the evaluated charged-particle production cross sections and measured data. Kerma coefficients are derived from the neutron cross sections, for major isotopes of H, C, N, O, Al, Si, P, Ca, Fe, Cu, W, Pb, and for ICRU-muscle, A-150 tissue-equivalent plastic, and other compounds important for treatment planning and dosimetry. Numerous comparisons are made between our kerma coefficients and experimental kerma coefficient data, to validate our results, and agreement is found to be good. An important quantity in neutron dosimetry is the kerma coefficient ratio of ICRU-muscle to A-150 plastic. When this ratio is calculated from our kerma coefficient data, and averaged over the neutron energy spectra for higher-energy clinical therapy beams [three p (68) + Be beams, and a d (48.5) + Be beam], a value of 0.94 +/- 0.03 is obtained. Kerma ratios for water to A-150 plastic, and carbon to oxygen, are also compared with measurements where available.

Pancreatic cancer: treatment with neutron irradiation alone and with chemotherapy.

PURPOSE: To evaluate neutron irradiation alone and with chemotherapy to treat inoperable pancreatic cancer. MATERIALS AND METHODS: Between 1977 and 1994, 173 patients (60 men, 113 women, aged 43-77 years [mean, 59 years]) with unresectable adenocarcinoma of the exocrine pancreas were treated, 106 with neutron irradiation alone and 67 with concomitant chemotherapy (fluorouracil [5-FU]). At follow-up, which was performed at 2-month intervals until death (range, 4-64 months), clinical status was recorded, noting the presence of overt metastasis and the onset of any major complications. Actuarial (Kaplan-Meier) survival tables were computed for both groups. RESULTS: For neutron irradiation alone and neutron irradiation plus chemotherapy, median survival times were 6 months and 9 months, respectively; actuarial survival rates at 3 years were 0 and 7%, respectively; major reactions (grade 3 or higher [scale of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer]) occurred in 19 (18%) and 17 (25%) patients, respectively; and severe complications (grade 4) occurred in five (5%) and four (6%) patients, respectively. Most deaths were due to metastatic disease rather than to failure of local control. CONCLUSIONS: Neutron irradiation obliterated pancreatic adenocarcinoma at the primary site but has no effect on long-term survival. With more effective concomitant chemotherapy to prevent metastasis, local control of pancreatic cancer with neutron irradiation could lead to increased long-term survival.

A feasibility study of 252Cf neutron brachytherapy, cisplatin + 5-FU chemo-adjuvant and accelerated hyperfractionated radiotherapy for advanced cervical cancer.

PURPOSE: To evaluate the feasibility and toxicity of 252Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers. METHODS AND MATERIALS: Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with 252Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m2) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m2/day x 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80-85 Gy-eq by external and intracavitary therapy and 60 Gy at the pelvic sidewalls. RESULTS: Patients tolerated the protocol well. There was 91% compliance with the chemotherapy and full compliance with the 252Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3-4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED). CONCLUSION: 252Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of 252Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. We found chemotherapy was more effective with the improved local tumor control.

[The shape of the absorbed dosage in neutron irradiation of a water phantom]. / Formirovanie pogloshchennoi dozy pri obluchenii vodnogo fantoma neitronami.

The paper is concerned with the results of experimental and estimated investigations into the spatial distribution of an absorbed dose and the spectrum of neutrons during irradiation of a water phantom by a P-3 beam of a BP-10 reactor. The ratio of densely ionizing and rarely ionizing components of an absorbed dose as well as the ratios between neutrons of different energetic groups were shown to undergo considerable changes with the penetration of reactor neutrons into the depth of a tissue-equivalent medium. The obtained results serve as basic data in various biomedical investigations using reactor neutron beams, including the planning of their use in cancer therapy.

Biomedical irradiation system for boron neutron capture therapy at the Kyoto University Reactor.

Physics studies related to radiation source, spectroscopy, beam quality, dosimetry, and biomedical applications using the Kyoto University Reactor Heavy Water Facility are described. Also, described are a Nickel Mirror Neutron Guide Tube and a Super Mirror Neutron Guide Tube that are used both for the measurement of boron concentration in phantom and living tissue and for precise measurements of neutron flux in phantom in the presence of both light and heavy water. Discussed are: (1) spectrum measurements using the time of flight technique, (2) the elimination of gamma rays and fast neutrons from a thermal neutron irradiation field, (3) neutron collimation without producing secondary gamma rays, (4) precise neutron flux measurements, dose estimation, and the measurement of boron concentration in tumor and its periphery using guide tubes, (5) the dose estimation of boron-10 for the first melanoma patient, and (6) special-purpose biological irradiation equipment. Other related subjects are also described.