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PubMed1994

Dose enhancement in fast neutron tumour therapy due to neutron captures in 10B.

High energy neutrons, applied in fast neutron tumour therapy, lose energy when passing through tissue and are at the end of their trajectories captured in nitrogen, hydrogen or other normally occurring elements. If the tissue contains 10B, which has a very high cross section for capture of thermal neutrons, then disintegration products of this process, helium and lithium ions, give a dose enhancement which, if the boron is targeted to tumour cells, may be beneficial. The dose enhancement was in the present study calculated as a function of the 10B concentration in the cells and as a function of different thermal neutron fluencies. If the tumour cells contained 10 or 100 microns 10B/g the average dose enhancement was about 20 or 200 mGy respectively. This was obtained with the thermal neutron fluency 2.0 x 10(10) n/cm2. The relative biological effectiveness of the neutron capture process is unknown but assuming the factor 2, these doses correspond to 0.04 or 0.4 CGE (cobolt-60 gray equivalent) respectively, which could directly be compared to the 2-3 Gy of low-LET radiation that is daily applied in conventional radiotherapy. However, if thermal or epithermal neutron fields are directly applied to the patients a hundred times higher thermal neutron fluency can be used. This gives, in the cases with 10 or 100 micrograms 10B/g, about a hundred times higher average doses so that 2-20 Gy, corresponding to about 4-40 CGE, can be given to the patients. Thus, a successful targeting with high amounts of 10B in the tumour cells gives a significant dose enhancement when applied in fast neutron therapy but it is then more reasonable to treat the patient directly with thermal or epithermal neutrons since the average dose enhancement in the latter case is about a hundred times higher and curable doses might be obtained by the tumour specific capture processes alone.

Boron Neutron Capture Therapy↗
PubMed1985

Review of clinical results of fast neutron therapy in the USA.

Fast neutron radiotherapy in the United States is entering a new era in which dedicated hospital-based generators with isocentric beam capability are replacing treatment facilities based on fixed beams extracted from physics accelerators. All available clinical data, however, come from the older facilities. The majority of randomized trials conducted in the U.S. have used neutrons in a mixed schedule with photons, in which the aim was to deliver two-fifths of the total dose with neutrons; the neutron dose per fraction was set as the estimated equivalent of 2 Gy photons in terms of late normal tissue injury. Overall treatment time was held constant compared with the control photon therapy regimens (usually six to eight weeks). Random studies of this type showed no evidence of a therapeutic gain in the treatment of advanced primary carcinomas of the head and neck, lung, uterine cervix, or pancreas. A statistically significant benefit in favor of the mixed schedule is presently apparent for local control and survival in patients with advanced prostate cancer, and for clearance of neck nodes in patients with advanced squamous carcinoma of the head and neck. Based on encouraging results in a pilot study of mixed scheduled irradiation preoperatively for bladder cancer, a random study was begun in 1981, but too few cases have been accrued for analysis. Other randomized trials comparing protracted neutron only regimens with photon therapy have been conducted. These were negative for lung and pancreatic cancer, but a suggestion of a therapeutic gain (with small patient numbers) has been observed for treatment of inoperable salivary gland tumors and advanced squamous carcinomas of the head and neck. Two large randomized studies of various neutron doses delivered as a boost to high grade astrocytomas after or concurrently with photon irradiation have failed to define any therapeutic window between tumor destruction and brain necrosis. Based on a reassessment of all the available clinical and radiobiological data, and taking advantage of the greater technical flexibility offered by hospital-based facilities, the strategy of fast neutron therapy for future trials has been changed. In these trials neutrons are being used in a twelve fraction, four week regimen to treat gross disease, with elective therapy being given wherever possible using low LET irradiation. Concomitantly, research is proceeding to define predictors of tumor response to high LET radiations in order to better select patients for fast neutron radiotherapy.

Fast Neutrons↗
PubMed2002

Direct effect in DNA radiolysis. Boron neutron capture enhancement of radiolysis in a medical fast-neutron beam.

SècheThis paper is devoted to the study of the molecular basis of the boron neutron capture enhancement of fast-neutron radiotherapy. Plasmid DNA was irradiated with a medical fast-neutron beam in the presence of either (10)B or (11)B. The number of induced SSBs and DSBs was much higher in samples containing (10)B compared to (11)B. The additional breaks are attributed to the nuclear reaction (10)B(n, alpha)(7)Li induced by the capture by (10)B of thermal neutrons produced in the medium by scattering and slowing down of neutrons. Irradiation in the presence of DMSO (OH radical scavenger) allows the number of nonscavengeable breaks to be determined. The ratio DSB/SSB is within the range of those observed with heavy ions, in good agreement with the hypothesis that the additional breaks are due to alpha particles and recoil lithium nuclei. The simulation of the energy deposition along the paths of the alpha and (7)Li particles allows the calculation of core and penumbra track volumes. Further, the number of plasmids encountered by the core and the penumbra was evaluated. Their number was compared to the nonscavengeable additional breaks. Since the two sets of values are of the same order of magnitude, we conclude that the nonscavengeable additional SSBs and DSBs could be due to direct effects.

Alpha Particles↗
PubMed1994

Boron neutron capture therapy: a mechanism for achieving a concomitant tumor boost in fast neutron radiotherapy.

PURPOSE: For many years neutron radiation has been used to treat malignant disease both as fast neutron radiotherapy and as thermal neutron induced boron neutron capture therapy (BNCT). To date, these two approaches have been used independently of one another due to the large difference in neutron energies each employs. In this paper we discuss the potential application of BNCT to enhance the therapeutic effectiveness of a fast neutron radiotherapy beam. METHODS AND MATERIALS: Measurements are presented for the thermal neutron component that is spontaneously developed as the University of Washington fast neutron radiotherapy beam penetrates a water phantom. The biological effect of this thermalized component on cells "tagged" with boron-10 (10B) is modeled mathematically and the expected change in cell survival calculated. The model is then extended to estimate the effect this enhanced cell killing would have for increased tumor control. RESULTS: The basic predictions of the model on changes in cell survival are verified with in vitro measurements using the V-79 cell line. An additional factor of 10-100 in tumor cell killing appears achievable with currently available 10B carriers using our present neutron beam. A Poisson model is then used to estimate the change in tumor control this enhanced cell killing would produce in various clinical situations and the effect is sufficiently large so as to be clinically relevant. It is also demonstrated that the magnitude of the thermalized component can be increased by a factor of 2-3 with relatively simple changes in the beam generating conditions. CONCLUSION: BNCT may provide a means of enhancing the therapeutic effectiveness of fast neutron radiotherapy in a wide variety of clinical situations and is an area of research that should be aggressively pursued.

Boron Neutron Capture Therapy↗
PubMed1998

Major compositional units of the moon: lunar prospector thermal and fast neutrons

Global maps of thermal and fast neutron fluxes from the moon suggest three end-member compositional units. A high thermal and low fast neutron flux unit correlates with the lunar highlands and is consistent with feldspathic rocks. The South Pole-Aitken basin and a strip that surrounds the nearside maria have intermediate thermal and fast neutron flux levels, consistent with more mafic rocks. There appears to be a smooth transition between the most mafic and feldspathic compositions, which correspond to low and high surface altitudes, respectively. The maria show low thermal and high fast neutron fluxes, consistent with basaltic rocks.

Journal Article↗
PubMed1996

Present status of fast neutron therapy in Asian countries.

In Asian countries, fast neutron therapy was first introduced at the National Institute of Radiological Sciences (NIRS), and followed by the Institute of Medical Science (IMS), Tokyo University, and Korea Cancer Center Hospital (KCCH). At NIRS, 2,129 patients were treated with d(30 MeV)+Be neutrons between 1975 and 1994. There were 274 patients referred for the treatment with P(50.5 MeV)+Be neutrons at KCCH during the period of 1986 through 1992. Unfortunately, fast neutron therapy performed at IMS was discontinued in 1991, where 458 patients had been treated with d(14 MeV)+Be neutrons since 1976. At NIRS, a vertical beam with multileaf collimator system was used for treatment of patients referred. The results showed that local control rates were 79% (19/24), 53% (14/26), and 89.3% (50/56) for carcinoma of the salivary gland, osteogenic sarcoma and carcinoma of the prostate, while complications for those were found to be 8.8, 8.3 and 17.8%, respectively. In the treatment of carcinoma of the lung, results were better for patients with adenocarcinoma than those with squamous cell carcinoma. Of 32 patients suffering from Pancoast tumor, 14 achieved local control, whereas 2 of 32 patients developed complications. On the other hand, salvage surgery was required in the treatment of malignant melanoma. In the treatment of malignant glioma, dose localization has to be improved in the target area to confirm local control. Experiences performed at KCCH have shown that, of 53 patients suffering from unresectable primary or recurrent rectal carcinomas, 28 achieved local control. It was concluded from the experiences with fast neutrons in Asian countries that adenocarcinomas as well as slowly growing tumors are indications for fast neutrons and that dose localization has to be improved in order to advance high LET radiation therapy. Clinical trials with 70 MeV protons started at NIRS in 1979, where the aim of study has been focused on treatment of choroidal melanoma, whereas, at Tsukuba University, 250 MeV protons have been used in the treatment of tumors deeply seated. Based on experiences of fast neutrons and protons, clinical trials with heavy ions initiated at NIRS in October 1994. Clinical studies with high LET radiations will be performed by using heavy ions in order to pursue indications of particle radiation therapy.

Fast Neutrons↗
PubMed1976

An historical survey of radiobiology and radiotherapy with fast neutrons.

The treatment of cancer using fast neutrons was first attempted from 1938 to 1942, only a few years after the identification of the particle in 1932. The radiobiological information which was available at that time was both inadequate and contradictory, and provided no definite rationale for using neutrons in preference to X-rays. The doses given were often too high, causing many patients to suffer severe late reactions. As a result, further attempts to use fast neutrons in radiotherapy were abandoned for nearly 30 years. Interest in the use of fast neutrons was stimulated again by the elucidation of the oxygen effect and the discovery that it was less for neutrons than for X-rays. Thus tumours containing hypoxic cells would be less protected against neutrons. Also the reduced repair of sublethal damage with neutrons provided at least a partial explanation of the miscalculation of dose in the early trial. This was confirmed by means of a series of experiments on pig skin, from which it was also concluded that late damage was not more severe after neutrons, compared with X-rays for a given degree of early damage. A new clinical trial began in 1966, and the results so far are encouraging. In order to relate radiotherapy experience with X-rays to neutrons, it is necessary to measure the relative biological effectiveness (RBE) of neutrons. This has been done for skin of man, pig, mouse and rat. Because of the smaller recovery from sublethal damage after neutrons, the RBE increases as the dose per fraction decreases, but the relationship between RBE and dose per fraction is the same for all four species. Similar information, but only for rodents, has been obtained for a variety of other normal tissues with both cyclotron-produced and monoenergetic 14 or 15 meV neutrons. Experiments with animal tumours have indicated that there might be a wide variation in RBE from tumour to tumour due both to the presence of hypoxic cells and to differences in their capacities to recover from sublethal damage after X-rays and neutrons. The largest series of experiments on one tumour shows that whereas certain fractionation techniques with X-rays may produce a poor tumour response for a given level of normal tissue damage, all the neutron regimes produced a similar, close to optimum result. There is no evidence from which to expect any special dangers from neutron irradiation, and their likely advantage is that they may provide a more reliable method of radiotherapy as well as sterilizing some tumours which are normally resistant to X-rays.

Animals↗
PubMed1983

[Clinical experience in patients with Pancoast's tumor treated by fast neutron therapy].

We review our results with fast neutron therapy in Pancoast's tumor, and compare them with results obtained by photon beam therapy. 13 patients with Pancoast's tumor were divided into two groups; Group I (8 patients) received fast neutron therapy. Group II (5 patients) were treated by voltage X-ray therapy. 1. Group I was comprised of 3 patients receiving mixed beam therapy (TDF 80-100) and 5 patients subjected to boost therapy. All group II patients received 3100 to 8000 rads. 2. Fast neutron therapy was effective in 7 patients. In group II, high voltage X-ray therapy was effective in only 3 patients. 3. Two group I patients are still alive without signs of recurrence. The others died with a mean survival of 11 months. All group II patients died; their mean survival was 4.2 months. Our results suggest that fast neutron therapy is suitable and effective in patients with Pancoast's tumor.

Adenoma↗
PubMed2002

Empirical description and Monte Carlo simulation of fast neutron pencil beams as basis of a treatment planning system.

The fast neutron beam, used for fast neutron therapy in Essen, is produced by the nuclear reaction of a 14 MeV cyclotron-based deuteron beam on a thick beryllium target. The resulting neutron beam has a continuous energy spectrum with a mean and a maximum energy equal to 5.5 and 18 MeV, respectively. The dose delivered to the patient is computed by a treatment planning system (TPS) based on an empirical model, in which the dose components (neutron and photon) are described by analytical functions. In order to improve the dose calculation, and thus to use the fast neutron beam for other applications (e.g., Boron Neutron Capture Enhancement of Fast Neutron Therapy), in this work we aim to develop a new TPS. For this purpose, a model based on pencil beams of mono-energetic neutrons has been created. The neutron energy ranged from 0.25 MeV up to 17.25 MeV by steps of 0.5 MeV in order to cover the energy range of the Essen facility. The Monte Carlo method was then used to simulate the transport of neutrons within such pencil beams in a homogeneous water phantom. By using Monte Carlo techniques, it is possible to distinguish the energy deposition due to a primary collision in water to that due to scattered neutrons. The energy deposition due to pencil beams of 2.224 MeV photons, coming from hydrogen neutron capture reaction in the phantom or in the collimator, was also determined. In order to complete this work, air filled cylinders have been introduced in the water phantom. It is shown that the resulting depth dose curves for primary neutrons can be easily derived using the homogeneous phantom, and that the description of the effect on scattered neutron dose distribution is more complex. In this work we demonstrate the relevance of Monte Carlo simulations of mono-energetic neutron pencil beams for purposes of neutron treatment planning. Some additional work is still required to describe a clinical situation (continuous energy neutron spectrum) as well as to experimentally validate the method described here.

Adipose Tissue↗
PubMed2004

Spectroscopic study of fast-neutron-irradiated chromatin.

The effects produced by fast neutrons (0-100 Gy) on chromatin structure were analyzed by (i) [1H]-NMR spectroscopy, (ii) time resolved spectroscopy, and (iii) fluorescence resonance energy transfer (FRET). Two types of chromatin were tested: (i) a chromatin from a normal tissue (liver of Wistar rats) and (ii) a chromatin from a tumoral tissue (Guerin limphotrope epithelioma, a rat solid tumor). The fast-neutron action on chromatin determines greater values of the [1H]-NMR transverse relaxation time, indicating a more injured structure. Time-resolved fluorescence measurements show that the relative contribution of the excited state lifetime of bound ethidium bromide to chromatin DNA diminishes with increasing irradiation doses. This reflects the damage that occurs in DNA structure: production of single- and double-strand breaks due to sugar and base modifications. By the FRET method, the distance between dansyl chloride and acridine orange coupled at chromatin was determined. This distance increases upon fast-neutron action. The radiosensitivity of the tumor tissue chromatin seems higher than that of the normal tissue chromatin, probably because of its higher (loose) euchromatin/(compact) heterochromatin ratio. As the values of the physical parameters analyzed are specific for a determined dose, the establishment of these parameters may constitute a criterion for the microdosimetry of chromatin radiolesions produced by fast neutrons.

Animals↗
PubMed1975

[Neutron therapy in the G.D.R. Fundamentals of fast neutron application in radiation treatment (author's transl)].

In 1972 GDR started with the treatment of tumor patients with fast neutrons on the base of oxygen-effect. That means a better sensitivity of radiation of anoxic cells against radiation with high LET in comparison to radiation of thin ionization. Every tumor contains some anoxic cells. Therefore a better effect is possible with doses that are tolerated by normal tissue. In the following the details of the problems are discussed.

Anaerobiosis↗
PubMed1988

Fast neutron radiotherapy--an overview.

Fast neutron radiotherapy has been employed worldwide in the last two decades in the treatment of a variety of advanced malignancies. The basic principles behind neutron treatment will be summarized in this article, along with results to date of a number of clinical trials evaluating the effectiveness and toxicity of neutron radiotherapy.

Clinical Trials as Topic↗
PubMed1989

Biological effectiveness of fast neutrons on a murine osteosarcoma.

The effect of fast neutrons and gamma rays on a murine osteosarcoma was studied. The NROS tumor, a radiation-induced osteosarcoma in a C3H mouse, was transplanted into the right hind legs of syngeneic female mice and locally irradiated with single or four daily doses of either fast neutrons or gamma rays. The NROS contained 13-30% hypoxic cells. It took approximately 7 days for the NROS tumor to show apparent reoxygenation following gamma ray irradiations. Two assays were used to determine the neutrons' relative biological effectiveness (RBE) to gamma rays: tumor growth delay time and tumor control dose. The largest RBE of 4.5 was obtained at the smallest dose of neutrons examined, followed by a gradual decrease down to 2.3. The tumor growth delay assay indicated that the RBE values of 2.6-3.1 after single doses of fast neutrons increased to 3.1-4.5 after four daily fractions. The 50% tumor control doses were 78.5 Gy and 33.0 Gy after single doses of gamma rays and fast neutrons, resulting in an RBE of 2.3. Fractionated doses increased the RBE to 2.6. Mitotic cells disappeared shortly after irradiation but reappeared 7 days after irradiation.

Animals↗
PubMed1990

Review of the clinical results of fast neutron therapy.

The clinical results reported from the different neutron therapy centres are reviewed. Fast neutrons were shown to be useful in the treatment of locally extended inoperable salivary gland tumours (average local control rates 67% for neutrons compared to 28% for photons). For paranasal sinuses and some tumours of the head and neck area, especially extended tumours with large fixed lymph nodes, neutrons could also be of interest. By contrast, the results obtained for brain tumours were, in general, disappointing. Neutrons were shown to be beneficial in the treatment of well differentiated soft tissue sarcomas, as well as to bone- and chondrosarcomas. For locally extended prostatic adenocarcinoma, a RTOG randomized trial gave local control rates of 77% for mixed schedule compared to 31% for photons. Neutrons could be useful also for palliative treatment of melanomas. Further studies are needed in order to evaluate the benefit of fast neutrons for other localizations such as uterine cervix, bladder and rectum. It can be concluded that fast neutrons could be of interest for about 10% of the radiotherapy patients, but it is likely that the new high-energy hospital-based cyclotrons will further extend the indications of neutron therapy. However, patient selection remains one of the main problems and there is a need for development of individual predictive tests.

Brain Neoplasms↗
PubMed2002

Involvement of TP53 in apoptosis induced in human lymphoblastoid cells by fast neutrons.

We investigated the involvement of TP53 in apoptosis induced by fast neutrons in cells of three human B-lymphoblast cell lines derived from the same donor and differing in TP53 status: TK6 (wild-type TP53), WTK1 (mutant TP53) and NH32 (knockout TP53). Cells were exposed to X rays or to fast neutrons at doses ranging from 0.5 to 8 Gy. Apoptosis was determined by measurements of the sub-G0 /G1-phase DNA content and by the externalization of phosphatidylserine. Fast neutrons induced extensive apoptosis in TK6 cells, as shown by the formation of hypodiploid particles, the externalization of phosphatidylserine, and the activation of caspases. In contrast, cell death was triggered at a significantly lower rate in cells lacking functional TP53. However, TP53-independent cell death also expressed the morphological and biochemical hallmarks of apoptosis. Proliferation tests and clonogenic assays showed that fast neutrons can nevertheless kill WTK1 and NH32 cells efficiently. The absence of functional TP53 only delays radiation-induced cell death, which is also mediated by caspases. These results indicate that fast-neutron irradiation activates two pathways to apoptosis and that the greater relative biological effectiveness of fast neutrons reflects mainly an increase in clonogenic cell death.

Apoptosis↗
PubMed1976

Transfer dosemeters for fast neutron sources.

The increasing use of fast neutron sources in radiobiology, radiotherapy, etc. makes dosimetry intercomparisons (intercalibrations) by mail desirable. After comparing the relative advantages and disadvantages of the various available integrating fast neutron detectors, fission fragment track etching was chosen because such detectors can be made sufficiently small, rugged, fading resistant, inexpensive and accurate. Using several combinations of 232Th or 237Np as fissile materials, and organic and inorganic track detectors, it was established that both automatic spark counting and visual track counting techniques can be developed to cover the desirable dose range (approximately 50-500 rad) with sufficient accuracy (sigma less than or equal to 5%). One possible source of errors is the overlapping size distributions of fission fragment and recoil particle tracks in organic foils exposed at high neutron energies. Several approaches to reduce this problem are discussed.

Fast Neutrons↗
PubMedDate not supplied

Determination of the neutron and photon spectra of a clinical fast neutron beam.

A simple technique to determine the neutron and photon spectra of a clinical fast neutron beam is described. This technique involves making narrow beam attenuation measurements with a pair of ionization chambers and an iterative fitting program to analyze the data. A method is also described for determining the first-guess neutron spectrum for input into the iterative program. The results of the analysis yield spectra suitable for use in dose calculation algorithms and dosimetry protocols. Presented here is the first-known published photon spectrum from a clinical machine.

Humans↗
PubMed1978

A new polycarbonate fast neutron personnel dosimeter.

Registration of fast-neutron-induced recoil and (n,alpha) tracks directly in sensitive polymers especially polycarbonate foils when etched by the electrochemical etching (ECE) method provides a simple, sensitive, and inexpensive means of fast neutron dosimetry. The wide dose range and a dose equivalent response, negligible fading rate, and insensitivity to X, beta, and gamma radiations make such a method feasible for many neutron dosimetry applications, especially personnel dosimetry. Due to very large size of the tracks, even the unaided eye can be used as a reading device.

Carbonates↗