Effects of tissue heterogeneity and comparisons of collapsed cone and Monte Carlo fast neutron patient dosimetry using the University of Washington clinical neutron therapy system (CNTS).

Fast neutron therapy is a high linear energy transfer (LET) radiation treatment modality offering advantages over low LET radiations. Multileaf collimator technology reduces normal-tissue dose (toxicity) and makes neutron therapy more comparable to MV x-ray treatments. Published clinical-trial and other experiences with fast neutron therapy are reported. Early comparative studies failed to consider differences in target-dose spatial conformality between x-ray and neutron treatments, which is especially important for organs-at-risk close to tumor targets. Treatments planning systems (TPS) for high-energy neutrons lag behind TPS tools for MV x-rays, creating challenges for comparative studies of clinical outcomes. A previously published Monte Carlo model of the University of Washington (UW) Clinical Neutron Therapy System (CNTS) is refined and integrated with the RayStation TPS as an external dose planning/verification tool. The collapsed cone (CC) dose calculations in the TPS are based on measured dose profiles and output factors in water, with the absolute dose determined using a tissue-equivalent ionization chamber. For comparison, independent (external) Monte Carlo simulation computes dose on a voxel-by-voxel basis using an atlas that maps Hounsfield Unit (HU) numbers to elemental composition and density. Although the CC algorithm in the TPS accurately computes neutron dose to water compared to Monte Carlo calculations, calculated dose to water differs from bone or tissue depending largely on hydrogen content. Therefore, the elemental composition of tissue and bone, rather than the material or electron density, affects fast neutron dose. While the CC algorithm suffices for reproducible patient dosimetry in fast neutron therapy, adopting methods that consider tissue heterogeneity would enhance patient-specific neutron dose accuracy relative to national standards for other types of ionizing radiation. Corrections for tissue composition have a significant impact on absolute dose and the relative biological effectiveness (RBE) of neutron treatments compared to other radiation types (MV x-rays, protons, and carbon ions).

Method of Measuring High-LET Particles Dose.

In boron neutron capture therapy, the total absorbed dose is the sum of four dose components with different relative biological effectiveness (RBE): boron dose, "nitrogen" dose, fast neutron dose and γ-ray dose. We present a new approach for measuring the first three doses. In this work, we provide the details of this method of dose measurement and results when this proposed method is employed.

Scattering kernels for fast neutron therapy treatment planning.

The University of Washington (UW) Clinical Neutron Therapy System (CNTS) has been used to treat over 3300 patients. Treatment planning for these patients is currently performed using an MV x-ray model in Pinnacle® adapted to fit measurements of fast neutron output factors, wedge factors, depth-dose and lateral profiles. While this model has provided an adequate representation of the CNTS for 3D conformal treatment planning, later versions of Pinnacle did not allow for isocentric gantry rotation machines with a source-to-axis distance of 150 cm. This restriction limited the neutron model to version 9.0 while the photon and electron treatment planning at the UW had moved on to newer versions. Also, intensity modulated neutron therapy (IMNT) is underdevelopment at the UW, and the Pinnacle neutron model developed cannot be used for inverse treatment planning. We have used the MCNP6 Monte Carlo code system to develop Collapsed Cone (CC) and Singular Value Decomposition (SVD) neutron scattering kernels suitable for integration into the RayStation treatment planning system. Kernels were generated for monoenergetic neutrons with energies ranging from 1 keV to 51 MeV, i.e. the energy range most relevant to the CNTS. Percent depth dose (PDD) profiles computed in RayStation for the CC and SVD kernels are in excellent agreement with each other for depths beyond the beam's dose build-up region (depths greater than about 1.7 cm) for open 2.8 × 2.8 cm2, 10.3 × 10.3 cm2, and 28.8 × 32.8 cm2 fields. Lateral profiles at several depths, as well as the PDD, calculated using the CC kernels in RayStation for the full CNTS energy spectrum pass a 3%/3 mm gamma test for field sizes of 2.8 × 2.8 cm2, 10.0 × 10.3 cm2, and 28.8 × 32.8 cm2.

Computational approach to determine the relative biological effectiveness of fast neutrons using the Geant4-DNA toolkit and a DNA atomic model from the Protein Data Bank.

This study proposes an innovative approach to estimate relative biological effectiveness (RBE) of fast neutrons using the Geant4 toolkit. The Geant4-DNA version cannot track heavy ions below 0.5 MeV/nucleon. In order to explore the impact of this issue, secondary particles are simulated instead of the primary low-energy neutrons. The Evaluated Nuclear Data File library is used to determine the cross sections for the elastic and inelastic interactions of neutrons with water and to find the contribution of each secondary particle spectrum. Two strategies are investigated in order to find the best possible approach and results. The first one takes into account only light particles, protons produced from elastic scattering, and α particles from inelastic scattering. Geantino particles are shot instead of heavy ions; hence all heavy ions are considered in the simulations, though their physical effects on DNA not. The second strategy takes into account all the heavy and light ions, although heavy ions cannot be tracked down to very low energies (E<0.5 MeV/nucleon). Our model is based on the combination of an atomic resolution DNA geometrical model and a Monte Carlo simulation toolkit for tracking particles. The atomic coordinates of the DNA double helix are extracted from the Protein Data Bank. Since secondary particle spectra are used instead of simulating the interaction of neutrons explicitly, this method reduces the computation times dramatically. Double-strand break induction is used as the end point for the estimation of the RBE of fast neutrons. ^{60}Co Î³ rays are used as the reference radiation quality. Both strategies succeed in reproducing the behavior of the RBE_{max} as a function of the incident neutron energy ranging from 0.1 to 14 MeV, including the position of its peak. A comparison of the behavior of the two strategies shows that for neutrons with energies less than 0.7 MeV, the effect of heavy ions would not be very significant, but above 0.7 MeV, heavy ions have an important role in neutron RBE.

Investigation of the neutron spectrum measurement method for dose evaluation in boron neutron capture therapy.

In boron neutron capture therapy, it is important to evaluate the dose administered to a patient's body outside the tumour area. The exposure dose is evaluated by calculation; however, the calculated value must be validated using a measured value. The dose evaluations based on the measured neutron spectrum are investigated. Multi-foil activation, combined with a LiCaAlF6 scintillation detector and an imaging plate, is proposed as a measurement method. The proposed method can measure the neutron spectrum at various points quickly.

Real-time detection of fast and thermal neutrons in radiotherapy with CMOS sensors.

The peripheral dose distribution is a growing concern for the improvement of new external radiation modalities. Secondary particles, especially photo-neutrons produced by the accelerator, irradiate the patient more than tens of centimeters away from the tumor volume. However the out-of-field dose is still not estimated accurately by the treatment planning softwares. This study demonstrates the possibility of using a specially designed CMOS sensor for fast and thermal neutron monitoring in radiotherapy. The 14 microns-thick sensitive layer and the integrated electronic chain of the CMOS are particularly suitable for real-time measurements in γ/n mixed fields. An experimental field size dependency of the fast neutron production rate, supported by Monte Carlo simulations and CR-39 data, has been observed. This dependency points out the potential benefits of a real-time monitoring of fast and thermal neutron during beam intensity modulated radiation therapies.

Commissioning optically stimulated luminescence in vivo dosimeters for fast neutron therapy.

PURPOSE: Clinical in vivo dosimeters intended for use with photon and electron therapies have not been utilized for fast neutron therapy because they are highly susceptible to neutron damage. The objective of this work was to determine if a commercial optically stimulated luminescence (OSL) in vivo dosimetry system could be adapted for use in fast neutron therapy. METHODS: A 50.5 MeV fast neutron beam generated by a clinical neutron therapy cyclotron was used to irradiate carbon doped aluminum oxide (Al2O3:C) optically simulated luminescence dosimeters (OSLDs) in a solid water phantom under standard calibration conditions, 150 cm SAD, 1.7 cm depth, and 10.3 × 10.0 cm field size. OSLD fading and electron trap depletion studies were performed with the OSLDs irradiated with 20 and 50 cGy and monitored over a 24-h period to determine the optimal time for reading the dosimeters during calibration. Four OSLDs per group were calibrated over a clinical dose range of 0-150 cGy. RESULTS: OSLD measurement uncertainties were lowered to within ±2%-3% of the expected dose by minimizing the effect of transient fading that occurs with neutron irradiation and maintaining individual calibration factors for each dosimeter. Dose dependent luminescence fading extended beyond the manufacturer's recommended 10 min period for irradiation with photon or electron beams. To minimize OSL variances caused by inconsistent fading among dosimeters, the observed optimal time for reading the OSLDs postirradiation was between 30 and 90 min. No field size, wedge factor, or gantry angle dependencies were observed in the OSLDs irradiated by the studied fast neutron beam. CONCLUSIONS: Measurements demonstrated that uncertainties less than ±3% were attainable in OSLDs irradiated with fast neutrons under clinical conditions. Accuracy and precision comparable to clinical OSL measurements observed with photons can be achieved by maintaining individual OSLD calibration factors and minimizing transient fading effects.

Simulation study of accelerator based quasi-mono-energetic epithermal neutron beams for BNCT.

Filtered neutron techniques were applied to produce quasi-mono-energetic neutron beams in the energy range of 1.5-7.5 keV at the accelerator port using the generated neutron spectrum from a Li (p, n) Be reaction. A simulation study was performed to characterize the filter components and transmitted beam lines. The feature of the filtered beams is detailed in terms of optimal thickness of the primary and additive components. A computer code named "QMNB-AS" was developed to carry out the required calculations. The filtered neutron beams had high purity and intensity with low contamination from the accompanying thermal, fast neutrons and γ-rays.

[Fast neutrons 6.3 MeV in the combined treatment of patients with local recurrence of breast cancer].

The article is devoted to the problem of treatment of patients with locally advanced breast cancer recurrences as well as a study of neutron therapy influence on normal tissues and various critical organs. The use of fast neutrons of 6.3 MeV in these patients is often the only treatment option. A 6-year survival rate of patients without repeated signs of recurrent breast cancer after neutron and neutron-photon therapy is 92.2 ± 5.7%.

[The use of fast neutrons in treatment of malignant tumors of the head and neck].

The article presents issues of the application of neutron therapy in the combined and radiation therapy for head and neck tumors. There were developed methods of neutron and neutron-photon therapy in pre- and postoperative periods as well as in stand-alone option in unresectable tumors. The data obtained clearly demonstrate the superiority of new ways over standard methods of treatment. Neutron therapy is satisfactorily tolerated and allows improving the results of combined and radiation therapy patients with malignant tumors of the head and neck.

Fast neutron radiotherapy in the treatment of malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a fatal disease lacking standardized treatment. We describe the use of fast neutron radiation therapy in MPM patients referred to the Department of Radiation Oncology at the University of Washington Medical Center. MATERIALS AND METHODS: Retrospective chart review of MPM patients receiving neutron radiotherapy treatment from 1980 to 2012. RESULTS: A total of 30 MPM patients received fast neutron radiotherapy as part of their treatment regimen. Median age at diagnosis was 59.6 years (range, 46.6 to 72.3 y). Eighteen patients received fast neutron radiotherapy as a component of trimodality treatment. Median overall survival was 20.3 months (range, 5.5 to 73.3 mo) with 1 patient censored at 34.8 months and all other patients with confirmed dates of death. One patient receiving radiotherapy alone as a palliative measure died during radiation treatment. One patient was unable to tolerate radiotherapy and stopped before completing prescribed treatment. On univariate analysis, Brigham Stage at presentation was a significant predictor of survival (P<0.01). No significant differences in survival were observed when comparing patients who received trimodality treatment compared to those who did not. CONCLUSIONS: Fast neutron radiotherapy may be utilized in the management of MPM patients. However, treatment with fast neutron radiotherapy did not significantly improvement outcome, even when used in a trimodality regimen.

A study on the optimum fast neutron flux for boron neutron capture therapy of deep-seated tumors.

High-energy neutrons, named fast neutrons which have a number of undesirable biological effects on tissue, are a challenging problem in beam designing for Boron Neutron Capture Therapy, BNCT. In spite of this fact, there is not a widely accepted criterion to guide the beam designer to determine the appropriate contribution of fast neutrons in the spectrum. Although a number of researchers have proposed a target value for the ratio of fast neutron flux to epithermal neutron flux, it can be shown that this criterion may not provide the optimum treatment condition. This simulation study deals with the determination of the optimum contribution of fast neutron flux in the beam for BNCT of deep-seated tumors. Since the dose due to these high-energy neutrons damages shallow tissues, delivered dose to skin is considered as a measure for determining the acceptability of the designed beam. To serve this purpose, various beam shaping assemblies that result in different contribution of fast neutron flux are designed. The performances of the neutron beams corresponding to such configurations are assessed in a simulated head phantom. It is shown that the previously used criterion, which suggests a limit value for the contribution of fast neutrons in beam, does not necessarily provide the optimum condition. Accordingly, it is important to specify other complementary limits considering the energy of fast neutrons. By analyzing various neutron spectra, two limits on fast neutron flux are proposed and their validity is investigated. The results show that considering these limits together with the widely accepted IAEA criteria makes it possible to have a more realistic assessment of sufficiency of the designed beam. Satisfying these criteria not only leads to reduction of delivered dose to skin, but also increases the advantage depth in tissue and delivered dose to tumor during the treatment time. The Monte Carlo Code, MCNP-X, is used to perform these simulations.

Secondary radiation dose during high-energy total body irradiation.

AIM: The goal of this work was to assess the additional dose from secondary neutrons and γ-rays generated during total body irradiation (TBI) using a medical linac X-ray beam. BACKGROUND: Nuclear reactions that occur in the accelerator construction during emission of high-energy beams in teleradiotherapy are the source of secondary radiation. Induced activity is dependent on the half-lives of the generated radionuclides, whereas neutron flux accompanies the treatment process only. MATERIALS AND METHODS: The TBI procedure using a 18 MV beam (Clinac 2100) was considered. Lateral and anterior-posterior/posterior-anterior fractions were investigated during delivery of 2 Gy of therapeutic dose. Neutron and photon flux densities were measured using neutron activation analysis (NAA) and semiconductor spectrometry. The secondary dose was estimated applying the fluence-to-dose conversion coefficients. RESULTS: The main contribution to the secondary dose is associated with fast neutrons. The main sources of γ-radiation are the following: (56)Mn in the stainless steel and (187)W of the collimation system as well as positron emitters, activated via (n,γ) and (γ,n) processes, respectively. In addition to 12 Gy of therapeutic dose, the patient could receive 57.43 mSv in the studied conditions, including 4.63 µSv from activated radionuclides. CONCLUSION: Neutron dose is mainly influenced by the time of beam emission. However, it is moderated by long source-surface distances (SSD) and application of plexiglass plates covering the patient body during treatment. Secondary radiation gives the whole body a dose, which should be taken into consideration especially when one fraction of irradiation does not cover the whole body at once.

[On the state and prospects of development of remote neutron therapy].

The state and prospects of remote neutron therapy were analyzed in this review. Years of experience with fast neutrons, both positive and negative, allow evaluating the most promising ways of further development of this area of radiation therapy. These include conducting targeted research for those tumors which received some encouraging results, a use of the combination of fast neutron therapy and conformal photon therapy as well as the creation of specialized medical facilities for neutron therapy based on optimization of both parameters of spatial distribution of the dose and radiobiological characteristics.

[Mixed (photon-neutron) therapy in complex treatment for locally advanced breast cancer].

Long term results of treatment of patients with locally advanced breast carcinoma with the use of mixed photon-neutron therapy (PNT) are presented. Among 201 patients with locally advanced breast cancer receiving radiation therapy, in 95 of them it was implemented as a combination of photon and neutron radiation therapy and in 106--in the form of mega-volt photon therapy (PT). Comparative evaluation of the long-term results of treatment proved the superiority of PNT. The immediate effect after PNT in the form of complete and partial response of tumor was registered in 87.4%, and after PT--in 49% of cases. Five-year and ten-year survival rates without signs of disease after PNT were 58.1% and 29.5%, and after PT--36.4% and 7.4% respectively. Substantial differences in toxicity of techniques were not observed.

Fast neutron radiotherapy for primary mucosal melanomas of the head and neck.

BACKGROUND: Primary head and neck mucosal melanomas (HNMMs) are rare tumors managed with surgery and/or radiotherapy and associated with poor outcomes. Given their radioresistance, high linear energy transfer radiotherapy with neutrons may improve local control. METHODS: We conducted a retrospective review of 14 patients with HNMM treated with neutrons at the University of Washington from 1990 to 2012. Five patients had T3 disease, 9 had T4 disease, 3 had regional nodal disease, and 4 had distant metastases at diagnosis. Primary sites were sinonasal (n=10), lip (n=2), and palate (n=2). Ten patients had initial surgical resection/debulking. RESULTS: Nine patients had gross residual disease, 6 had complete response, and 3 had partial response. Local control was achieved in 79% until death or last follow-up, and 50% developed distant metastases. Kaplan-Meier 5-year local control was 66% and overall survival was 21%. CONCLUSION: High rates of locoregional control were achieved with neutrons, despite the presence of gross disease. Survival was limited by early distant metastases.

Validation of the Pinnacle³ photon convolution-superposition algorithm applied to fast neutron beams.

We evaluate a photon convolution-superposition algorithm used to model a fast neutron therapy beam in a commercial treatment planning system (TPS). The neutron beam modeled was the Clinical Neutron Therapy System (CNTS) fast neutron beam produced by 50 MeV protons on a Be target at our facility, and we implemented the Pinnacle3 dose calculation model for computing neutron doses. Measured neutron data were acquired by an IC30 ion chamber flowing 5 cc/min of tissue equivalent gas. Output factors and profile scans for open and wedged fields were measured according to the Pinnacle physics reference guide recommendations for photon beams in a Wellhofer water tank scanning system. Following the construction of a neutron beam model, computed doses were then generated using 100 monitor units (MUs) beams incident on a water-equivalent phantom for open and wedged square fields, as well as multileaf collimator (MLC)-shaped irregular fields. We compared Pinnacle dose profiles, central axis doses, and off-axis doses (in irregular fields) with 1) doses computed using the Prism treatment planning system, and 2) doses measured in a water phantom and having matching geometry to the computation setup. We found that the Pinnacle photon model may be used to model most of the important dosimetric features of the CNTS fast neutron beam. Pinnacle-calculated dose points among open and wedged square fields exhibit dose differences within 3.9 cGy of both Prism and measured doses along the central axis, and within 5 cGy difference of measurement in the penumbra region. Pinnacle dose point calculations using irregular treatment type fields showed a dose difference up to 9 cGy from measured dose points, although most points of comparison were below 5 cGy. Comparisons of dose points that were chosen from cases planned in both Pinnacle and Prism show an average dose difference less than 0.6%, except in certain fields which incorporate both wedges and heavy blocking of the central axis. All clinical cases planned in both Prism and Pinnacle were found to be comparable in terms of dose-volume histograms and spatial dose distribution following review by the treating clinicians. Variations were considered minor and within clinically acceptable limits by the treating clinicians. The Pinnacle TPS has sufficient computational modeling ability to adequately produce a viable neutron model for clinical use in treatment planning.

Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy?

BACKGROUND AND PURPOSE: To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams. MATERIALS AND METHODS: Neutrons at iThemba LABS are produced by the reaction of 66MeV protons on a beryllium target. A median dose 20.4Gy, in 12 fractions in 4weeks or 15 fractions in 5weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours. RESULTS: Locoregional control was 60.6% at 5years and 39.1% at 10years and DSS was 66.8% and 53.7% at 5 and 10years respectively. In the univariate analysis T4, >4cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease. CONCLUSIONS: Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.

Optimization of the beam shaping assembly in the D-D neutron generators-based BNCT using the response matrix method.

Optimization of the Beam Shaping Assembly (BSA) has been performed using the MCNP4C Monte Carlo code to shape the 2.45 MeV neutrons that are produced in the D-D neutron generator. Optimal design of the BSA has been chosen by considering in-air figures of merit (FOM) which consists of 70 cm Fluental as a moderator, 30 cm Pb as a reflector, 2mm (6)Li as a thermal neutron filter and 2mm Pb as a gamma filter. The neutron beam can be evaluated by in-phantom parameters, from which therapeutic gain can be derived. Direct evaluation of both set of FOMs (in-air and in-phantom) is very time consuming. In this paper a Response Matrix (RM) method has been suggested to reduce the computing time. This method is based on considering the neutron spectrum at the beam exit and calculating contribution of various dose components in phantom to calculate the Response Matrix. Results show good agreement between direct calculation and the RM method.

[The clinical course of thyroid cancer following its combined treatment with the use of fast-neutron therapy in the patients at the high risk of relapses].

A few patients presenting with thyroid cancer characterized by the high risk of relapses are reported. Their combined treatment included therapy using fast-neuron with the energy of 6.3 MeV. The immediate and late results of the treatment of the reported cases are evaluated. The experience gained during the study gives evidence of the fairly good tolerability of the described radiotherapeutic modality producing neither acute radiation reactions nor lesions in the irradiated tissues and organs. Moreover, the treatment is described as a highly effective one.