Discordance in acute gastrointestinal toxicity between synchrotron-based proton and linac-based electron ultra-high dose rate irradiation.

Purpose: Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates. Methods and Materials: We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s). Results: The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups). Conclusions: Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.

Benchmark measurements and simulations of dose perturbations due to metallic spheres in proton beams.

Monte Carlo simulations are increasingly used for dose calculations in proton therapy due to its inherent accuracy. However, dosimetric deviations have been found using Monte Carlo code when high density materials are present in the proton beam line. The purpose of this work was to quantify the magnitude of dose perturbation caused by metal objects. We did this by comparing measurements and Monte Carlo predictions of dose perturbations caused by the presence of small metal spheres in several clinical proton therapy beams as functions of proton beam range, spread-out Bragg peak width and drift space. Monte Carlo codes MCNPX, GEANT4 and Fast Dose Calculator (FDC) were used. Generally good agreement was found between measurements and Monte Carlo predictions, with the average difference within 5% and maximum difference within 17%. The modification of multiple Coulomb scattering model in MCNPX code yielded improvement in accuracy and provided the best overall agreement with measurements. Our results confirmed that Monte Carlo codes are well suited for predicting multiple Coulomb scattering in proton therapy beams when short drift spaces are involved.

A procedure to determine the planar integral spot dose values of proton pencil beam spots.

PURPOSE: Planar integral spot dose (PISD) of proton pencil beam spots (PPBSs) is a required input parameter for beam modeling in some treatment planning systems used in proton therapy clinics. The measurement of PISD by using commercially available large area ionization chambers, like the PTW Bragg peak chamber (BPC), can have large uncertainties due to the size limitation of these chambers. This paper reports the results of our study of a novel method to determine PISD values from the measured lateral dose profiles and peak dose of the PPBS. METHODS: The PISDs of 72.5, 89.6, 146.9, 181.1, and 221.8 MeV energy PPBSs were determined by area integration of their planar dose distributions at different depths in water. The lateral relative dose profiles of the PPBSs at selected depths were measured by using small volume ion chambers and were investigated for their angular anisotropies using Kodak XV films. The peak spot dose along the beam's central axis (D(0)) was determined by placing a small volume ion chamber at the center of a broad field created by the superposition of spots at different locations. This method allows eliminating positioning uncertainties and the detector size effect that could occur when measuring it in single PPBS. The PISD was then calculated by integrating the measured lateral relative dose profiles for two different upper limits of integration and then multiplying it with corresponding D(0). The first limit of integration was set to radius of the BPC, namely 4.08 cm, giving PISD(RBPC). The second limit was set to a value of the radial distance where the profile dose falls below 0.1% of the peak giving the PISD(full). The calculated values of PISD(RBPC) obtained from area integration method were compared with the BPC measured values. Long tail dose correction factors (LTDCFs) were determined from the ratio of PISD(full)∕PISD(RBPC) at different depths for PPBSs of different energies. RESULTS: The spot profiles were found to have angular anisotropy. This anisotropy in PPBS dose distribution could be accounted in a reasonable approximate manner by taking the average of PISD values obtained using the in-line and cross-line profiles. The PISD(RBPC) values fall within 3.5% of those measured by BPC. Due to inherent dosimetry challenges associated with PPBS dosimetry, which can lead to large experimental uncertainties, such an agreement is considered to be satisfactory for validation purposes. The PISD(full) values show differences ranging from 1 to 11% from BPC measured values, which are mainly due to the size limitation of the BPC to account for the dose in the long tail regions of the spots extending beyond its 4.08 cm radius. The dose in long tail regions occur both for high energy beams such as 221.8 MeV PPBS due to the contributions of nuclear interactions products in the medium, and for low energy PPBS because of their larger spot sizes. The calculated LTDCF values agree within 1% with those determined by the Monte Carlo (MC) simulations. CONCLUSIONS: The area integration method to compute the PISD from PPBS lateral dose profiles is found to be useful both to determine the correction factors for the values measured by the BPC and to validate the results from MC simulations.

Technical note: Monte Carlo study of the mechanism of proton-boron fusion therapy.

PURPOSE: Proton beam therapy has been found to have enhanced biological effectiveness in targets that contain the boron isotope 11 B, with the alpha particles resulting from the p + 11 B → 3α reaction being hypothesized as the mechanism; in this study, we aimed to elucidate the causes of the enhanced biological effectiveness of proton-boron fusion therapy by performing a detailed Monte Carlo study of the p + 11 B → 3α reaction in a phantom geometry. METHODS: We utilized the Geant4 toolkit to create Monte Carlo particle physics simulations. These simulations consisted of a proton beam with a range 30 mm, creating a Spread-Out Bragg Peak with a modulation width of 10 mm, directed into a water phantom containing a region of boron material. Energy deposition, particle energy, and particle fluence were scored along the path of the beam and grouped by particle species. The scoring was performed using a series of cylindrical volumes with a radius of 2.5 mm and depth of 0.1 mm, constructed such that the depth was parallel to the proton beam. Root was then used to perform the data analysis. RESULTS: Our simulations showed that the dose delivered by alpha particles produced by p + 11 B → 3α was several orders of magnitude lower than the dose delivered directly by protons, even when the boron uptake region was comprised entirely of natural boron or pure 11 B. CONCLUSIONS: Our findings do not support the theory that an alpha particle-based mechanism is responsible for the enhanced biological effectiveness of proton-boron fusion therapy. We conclude that any enhanced biological effect seen in experimental studies was not caused by fusion reactions between protons and 11 B nuclei. However, it is necessary to reproduce the past experiments that indicated significant dose enhancement.

Optimization of FLASH proton beams using a track-repeating algorithm.

BACKGROUND: Radiation with high dose rate (FLASH) has shown to reduce toxicities to normal tissues around the target and maintain tumor control with the same amount of dose compared to conventional radiation. This phenomenon has been widely studied in electron therapy, which is often used for shallow tumor treatment. Proton therapy is considered a more suitable treatment modality for deep-seated tumors. The feasibility of FLASH proton therapy has recently been demonstrated by a series of pre- and clinical trials. One of the challenges is to efficiently generate wide enough dose distributions in both lateral and longitudinal directions to cover the entire tumor volume. The goal of this paper is to introduce a set of automatic FLASH proton beam optimization algorithms developed recently. PURPOSE: To develop a fast and efficient optimizer for the design of a passive scattering proton FLASH radiotherapy delivery at The University of Texas MD Anderson Proton Therapy Center, based on the fast dose calculator (FDC). METHODS: A track-repeating algorithm, FDC, was validated versus Geant4 simulations and applied to calculate dose distributions in various beamline setups. The design of the components was optimized to deliver homogeneous fields with well-defined diameters between 11.0 and 20.5 mm, as well as a spread-out Bragg peak (SOBP) with modulations between 8.5 and 39.0 mm. A ridge filter, a high-Z material scatterer, and a collimator with range compensator were inserted in the beam path, and their shapes and sizes were optimized to spread out the Bragg peak, widen the beam, and reduce the penumbra. The optimizer was developed and tested using two proton energies (87.0 and 159.5 MeV) in a variety of beamline arrangements. Dose rates of the optimized beams were estimated by scaling their doses to those of unmodified beams. RESULTS: The optimized 87.0-MeV beams, with a distance from the beam pipe window to the phantom surface (window-to-surface distance [WSD]) of 550 mm, produced an 8.5-mm-wide SOBP (proximal 90% to distal 90% of the maximum dose); 14.5, 12.0, and 11.0-mm lateral widths at the 50%, 80%, and 90% dose location, respectively; and a 2.5-mm penumbra from 80% to 20% in the lateral profile. The 159.5-MeV beam had an SOBP of 39.0 mm and lateral widths of 20.5, 15.0, and 12.5 mm at 50%, 80%, and 90% dose location, respectively, when the WSD was 550 mm. Wider lateral widths were obtained with increased WSD. The SOBP modulations changed when the ridge filters with different characteristics were inserted. Dose rates on the beam central axis for all optimized beams (other than the 87.0-MeV beam with 2000-mm WSD) were above that needed for the FLASH effect threshold (40 Gy/s) except at the very end of the depth dose profile scaling with a dose rate of 1400 Gy/s at the Bragg peak in the unmodified beams. The optimizer was able to instantly design the individual beamline components for each of the beamline setups, without the need of time intensive iterative simulations. CONCLUSION: An efficient system, consisting of an optimizer and an FDC have been developed and validated in a variety of beamline setups, comprising two proton energies, several WSDs, and SOBPs. The set of automatic optimization algorithms produces beam shaping element designs efficiently and with excellent quality.

Effect of boron compounds on the biological effectiveness of proton therapy.

PURPOSE: We assessed whether adding sodium borocaptate (BSH) or 4-borono-l-phenylalanine (BPA) to cells irradiated with proton beams influenced the biological effectiveness of those beams against prostate cancer cells to investigate if the alpha particles generated through proton-boron nuclear reactions would be sufficient to enhance the biological effectiveness of the proton beams. METHODS: We measured clonogenic survival in DU145 cells treated with 80.4-ppm BSH or 86.9-ppm BPA, or their respective vehicles, after irradiation with 6-MV X-rays, 1.2-keV/µm (low linear energy transfer [LET]) protons, or 9.9-keV/µm (high-LET) protons. We also measured γH2AX and 53BP1 foci in treated cells at 1 and 24 h after irradiation with the same conditions. RESULTS: We found that BSH radiosensitized DU145 cells across all radiation types. However, no difference was found in relative radiosensitization, characterized by the sensitization enhancement ratio or the relative biological effectiveness, for vehicle- versus BSH-treated cells. No differences were found in numbers of γH2AX or 53BP1 foci or γH2AX/53BP1 colocalized foci for vehicle- versus BSH-treated cells across radiation types. BPA did not radiosensitize DU145 cells nor induced any significant differences when comparing vehicle- versus BPA-treated cells for clonogenic cell survival or γH2AX and 53BP1 foci or γH2AX/53BP1 colocalized foci. CONCLUSIONS: Treatment with 11 B, at concentrations of 80.4 ppm from BSH or 86.9 ppm from BPA, had no effect on the biological effectiveness of proton beams in DU145 prostate cancer cells. Our results agree with published theoretical calculations indicating that the contribution of alpha particles from such reactions to the total absorbed dose and biological effectiveness is negligible. We also found that BSH radiosensitized DU145 cells to X-rays, low-LET protons, and high-LET protons but that the radiosensitization was not related to DNA damage.

Design and validation of a synchrotron proton beam line for FLASH radiotherapy preclinical research experiments.

PURPOSE: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron-based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread-out Bragg peak (SOBP) under FLASH conditions. METHODS: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian-like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low-dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam-shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm3 of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs. RESULTS: The designed and fabricated devices were used to produce 10-, 15-, and 20-mm diameter, circular field sizes and 10-, 15-, and 20-mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high-accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments. CONCLUSIONS: It is feasible to use synchrotron-generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon.

Adaptation and dosimetric commissioning of a synchrotron-based proton beamline for FLASH experiments.

Objective. Irradiation with ultra-high dose rates (>40 Gy s-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length and size of accelerating cycles, repurposing the reference monitor for dose control, and expanding the field size with a custom double-scattering system. We performed the dosimetric commissioning with measurements using an Advanced Markus chamber and EBT-XD films as well as with Monte Carlo simulations.Main results. Through adaptations, we have successfully achieved FLASH irradiation conditions, with an average dose rate of up to 375 Gy s-1. The Advanced Markus chamber was shown to be appropriate for absolute dose calibration under our FLASH conditions with a recombination factor ranging from 1.002 to 1.006 because of the continuous nature of our synchrotron-based proton delivery within a spill. Additionally, the absolute dose measured using the Advanced Markus chamber and EBT-XD films agreed well, with average and maximum differences of 0.32% and 1.63%, respectively. We also performed a comprehensive temporal analysis for FLASH spills produced by our system, which helped us identify a unique relationship between the average dose rate and the dose in our FLASH irradiation.Significance.We have established a synchrotron-based proton FLASH irradiation platform with accurate and precise dosimetry that is suitable for pre-clinical biology experiments. The unique time structure of the FLASH irradiation produced by our synchrotron-based system may shed new light onto the mechanism behind the FLASH effect.

Roadmap: helium ion therapy.

Helium ion beam therapy for the treatment of cancer was one of several developed and studied particle treatments in the 1950s, leading to clinical trials beginning in 1975 at the Lawrence Berkeley National Laboratory. The trial shutdown was followed by decades of research and clinical silence on the topic while proton and carbon ion therapy made debuts at research facilities and academic hospitals worldwide. The lack of progression in understanding the principle facets of helium ion beam therapy in terms of physics, biological and clinical findings persists today, mainly attributable to its highly limited availability. Despite this major setback, there is an increasing focus on evaluating and establishing clinical and research programs using helium ion beams, with both therapy and imaging initiatives to supplement the clinical palette of radiotherapy in the treatment of aggressive disease and sensitive clinical cases. Moreover, due its intermediate physical and radio-biological properties between proton and carbon ion beams, helium ions may provide a streamlined economic steppingstone towards an era of widespread use of different particle species in light and heavy ion therapy. With respect to the clinical proton beams, helium ions exhibit superior physical properties such as reduced lateral scattering and range straggling with higher relative biological effectiveness (RBE) and dose-weighted linear energy transfer (LETd) ranging from ∼4 keVµm-1to ∼40 keVµm-1. In the frame of heavy ion therapy using carbon, oxygen or neon ions, where LETdincreases beyond 100 keVµm-1, helium ions exhibit similar physical attributes such as a sharp lateral penumbra, however, with reduced radio-biological uncertainties and without potentially spoiling dose distributions due to excess fragmentation of heavier ion beams, particularly for higher penetration depths. This roadmap presents an overview of the current state-of-the-art and future directions of helium ion therapy: understanding physics and improving modeling, understanding biology and improving modeling, imaging techniques using helium ions and refining and establishing clinical approaches and aims from learned experience with protons. These topics are organized and presented into three main sections, outlining current and future tasks in establishing clinical and research programs using helium ion beams-A. Physics B. Biological and C. Clinical Perspectives.

Commissioning of the discrete spot scanning proton beam delivery system at the University of Texas M.D. Anderson Cancer Center, Proton Therapy Center, Houston.

PURPOSE: To describe a summary of the clinical commissioning of the discrete spot scanning proton beam at the Proton Therapy Center, Houston (PTC-H). METHODS: Discrete spot scanning system is composed of a delivery system (Hitachi ProBeat), an electronic medical record (Mosaiq V 1.5), and a treatment planning system (TPS) (Eclipse V 8.1). Discrete proton pencil beams (spots) are used to deposit dose spot by spot and layer by layer for the proton distal ranges spanning from 4.0 to 30.6 g/cm2 and over a maximum scan area at the isocenter of 30 x 30 cm2. An arbitrarily chosen reference calibration condition has been selected to define the monitor units (MUs). Using radiochromic film and ion chambers, the authors have measured spot positions, the spot sizes in air, depth dose curves, and profiles for proton beams with various energies in water, and studied the linearity of the dose monitors. In addition to dosimetric measurements and TPS modeling, significant efforts were spent in testing information flow and recovery of the delivery system from treatment interruptions. RESULTS: The main dose monitors have been adjusted such that a specific amount of charge is collected in the monitor chamber corresponding to a single MU, following the IAEA TRS 398 protocol under a specific reference condition. The dose monitor calibration method is based on the absolute dose per MU, which is equivalent to the absolute dose per particle, the approach used by other scanning beam institutions. The full width at half maximum for the spot size in air varies from approximately 1.2 cm for 221.8 MeV to 3.4 cm for 72.5 MeV. The measured versus requested 90% depth dose in water agrees to within 1 mm over ranges of 4.0-30.6 cm. The beam delivery interlocks perform as expected, guarantying the safe and accurate delivery of the planned dose. CONCLUSIONS: The dosimetric parameters of the discrete spot scanning proton beam have been measured as part of the clinical commissioning program, and the machine is found to function in a safe manner, making it suitable for patient treatment.

An MCNPX Monte Carlo model of a discrete spot scanning proton beam therapy nozzle.

PURPOSE: The purposes of this study were to validate a discrete spot scanning proton beam nozzle using the Monte Carlo (MC) code MCNPX and use the MC validated model to investigate the effects of a low-dose envelope, which surrounds the beam's central axis, on measurements of integral depth dose (IDD) profiles. METHODS: An accurate model of the discrete spot scanning beam nozzle from The University of Texas M. D. Anderson Cancer Center (Houston, Texas) was developed on the basis of blueprints provided by the manufacturer of the nozzle. The authors performed simulations of single proton pencil beams of various energies using the standard multiple Coulomb scattering (MCS) algorithm within the MCNPX source code and a new MCS algorithm, which was implemented in the MCNPX source code. The MC models were validated by comparing calculated in-air and in-water lateral profiles and percentage depth dose profiles for single pencil beams with their corresponding measured values. The models were then further tested by comparing the calculated and measured three-dimensional (3-D) dose distributions. Finally, an IDD profile was calculated with different scoring radii to determine the limitations on the use of commercially available plane-parallel ionization chambers to measure IDD. RESULTS: The distance to agreement, defined as the distance between the nearest positions of two equivalent distributions with the same value of dose, between measured and simulated ranges was within 0.13 cm for both MCS algorithms. For low and intermediate pencil beam energies, the MC simulations using the standard MCS algorithm were in better agreement with measurements. Conversely, the new MCS algorithm produced better results for high-energy single pencil beams. The IDD profile calculated with cylindrical tallies with an area equivalent to the area of the largest commercially available ionization chamber showed up to 7.8% underestimation of the integral dose in certain depths of the IDD profile. CONCLUSIONS: The authors conclude that a combination of MCS algorithms is required to accurately reproduce experimental data of single pencil beams and 3-D dose distributions for the scanning beam nozzle. In addition, the MC simulations showed that because of the low-dose envelope, ionization chambers with radii as large as 4.08 cm are insufficient to accurately measure IDD profiles for a 221.8 MeV pencil beam in the scanning beam nozzle.

Application of a fast proton dose calculation algorithm to a thorax geometry.

Treatment planning in proton therapy requires the calculation of absorbed dose distributions on beam shaping components and the patient anatomy. Analytical pencil-beam dose algorithms commonly used are not always accurate enough. The Monte Carlo approach is more accurate but extremely computationally intensive. The Fast Dose Calculator, a track-repeating algorithm, has been proposed as an alternative fast and accurate dose calculation. In this work FDC is applied to a proton therapy patient thoracic anatomy.

Monte Carlo Simulations of Neutron Ambient Dose Equivalent in a Novel Proton Therapy Facility Design.

PURPOSE: The neutron shielding properties of the concrete structures of a proposed proton therapy facility were evaluated with help of the Monte Carlo technique. The planned facility's design omits the typical maze-structured entrances to the treatment rooms to facilitate more efficient access and, instead, proposes the use of massive concrete/steel doors. Furthermore, straight conduits in the treatment room walls were used in the design of the facility, necessitating a detailed investigation of the neutron radiation outside the rooms to determine if the design can be applied without violating existing radiation protection regulations. This study was performed to investigate whether the operation of a proton therapy unit using such a facility design will be in compliance with radiation protection requirements. METHODS: A detailed model of the planned proton therapy expansion project of the University of Texas, M. D. Anderson Cancer Center in Houston, Texas, was produced to simulate secondary neutron production from clinical proton beams using the MCNPX Monte Carlo radiation transport code. Neutron spectral fluences were collected at locations of interest and converted to ambient dose equivalents using an in-house code based on fluence to dose-conversion factors provided by the International Commission on Radiological Protection. RESULTS AND CONCLUSIONS: At all investigated locations of interest, the ambient dose equivalent values were below the occupational dose limits and the dose limits for individual members of the public. The impact of straight conduits was negligible because their location and orientation were such that no line of sight to the neutron sources (ie, the isocenter locations) was established. Finally, the treatment room doors were specially designed to provide spatial efficiency and, compared with traditional maze designs, showed that while it would be possible to achieve a lower neutron ambient dose equivalent with a maze, the increased spatial (and financial) requirements may offset this advantage.

Mapping the Relative Biological Effectiveness of Proton, Helium and Carbon Ions with High-Throughput Techniques.

Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LETd), and dose-mean lineal energy (yd) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were yd-dependent. Both helium and carbon ions achieved maximum RBEs within specific yd ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as yd and are ion specific.

Monte Carlo study shows no significant difference in second cancer risk between 6- and 18-MV intensity-modulated radiation therapy.

PURPOSE: To evaluate the photon and neutron out-of-field dose equivalents from 6- and 18-MV intensity-modulated radiation therapy (IMRT) and to investigate the impact of the differences on the associated risk of induced second malignancy using a Monte Carlo model. METHODS AND MATERIALS: A Monte Carlo model created with MCNPX was used to calculate the out-of-field photon dose and neutron dose equivalent from simulated IMRT of the prostate conducted at beam energies of 6 and 18MV. The out-of-field dose equivalent was calculated at the locations of sensitive organs in an anthropomorphic phantom. Based on these doses, the risk of secondary malignancy was calculated based on organ-, gender-, and age-specific risk coefficients for a 50-year-old man. RESULTS: The Monte Carlo model predicted much lower neutron dose equivalents than had been determined previously. Further analysis illuminated the large uncertainties in the neutron dose equivalent and demonstrated the need for better determination of this value, which plays a large role in estimating the risk of secondary malignancies. The Monte Carlo calculations found that the differences in the risk of secondary malignancies conferred by high-energy IMRT versus low-energy IMRT are minimal and insignificant, contrary to prior findings. CONCLUSIONS: The risk of secondary malignancy associated with high-energy radiation therapy may not be as large as previously reported, and likely should not deter the use of high-energy beams. However, the large uncertainties in neutron dose equivalents at specific locations within the patient warrant further study so that the risk of secondary cancers can be estimated with greater accuracy.

Stereotactic radiotherapy for lung cancer using a flattening filter free Clinac.

The objective of this study was to assess the feasibility of stereotactic radiotherapy for early stage lung cancer using photon beams from a Varian Clinac accelerator operated without a flattening filter. Treatment plans were generated for 10 lung cancer patients with isolated lesions less than 3 cm in diameter. For each patient, two plans were generated, one with and one without the flattening filter. Plans were generated with Eclipse 8.0 (Varian Medical Systems) commissioned with beam data measured on a Clinac 21EX (Varian Medical Systems) operated with and without the flattening filter. Removal of the flattening filter increased the dose rate. The median beam-on time per field was reduced from 25 sec (with the filter) to 11 sec (without the filter), increasing the feasibility of breath-hold treatments and the efficiency of gated treatments. Differences in a dose heterogeneity index for the planning target volume between plans with flattened and unflattened beams were statistically insignificant. Differences in mean doses to organs at risk were small, typically about 10 cGy over the entire treatment. The study concludes that radiotherapy with unflattened beams is feasible and requires substantially less beam-on time, facilitating breath-hold and gating techniques.

REDUCING STRAY RADIATION DOSE FOR A PEDIATRIC PATIENT RECEIVING PROTON CRANIOSPINAL IRRADIATION.

The aim of this study was to quantify stray radiation dose from neutrons emanating from a proton treatment unit and to evaluate methods of reducing this dose for a pediatric patient undergoing craniospinal irradiation. The organ equivalent doses and effective dose from stray radiation were estimated for a 30.6-Gy treatment using Monte Carlo simulations of a passive scattering treatment unit and a patient-specific voxelized anatomy. The treatment plan was based on computed tomography images of a 10-yr-old male patient. The contribution to stray radiation was evaluated for the standard nozzle and for the same nozzle but with modest modifications to suppress stray radiation. The modifications included enhancing the local shielding between the patient and the primary external neutron source and increasing the distance between them. The effective dose from stray radiation emanating from the standard nozzle was 322 mSv; enhancements to the nozzle reduced the effective dose by as much as 43%. These results add to the body of evidence that modest enhancements to the treatment unit can reduce substantially the effective dose from stray radiation.

Comparing 2 Monte Carlo Systems in Use for Proton Therapy Research.

PURPOSE: Several Monte Carlo transport codes are available for medical physics users. To ensure confidence in the accuracy of the codes, they must be continually cross-validated. This study provides comparisons between MC2 and Tool for Particle Simulation (TOPAS) simulations, that is, between medical physics applications for Monte Carlo N-Particle Transport Code (MCNPX) and Geant4. MATERIALS AND METHODS: Monte Carlo simulations were repeated with 2 wrapper codes: TOPAS (based on Geant4) and MC2 (based on MCNPX). Simulations increased in geometrical complexity from a monoenergetic beam incident on a water phantom, to a monoenergetic beam incident on a water phantom with a bone or tissue slab at various depths, to a spread-out Bragg peak incident on a voxelized computed tomography (CT) geometry. The CT geometry cases consisted of head and neck tissue and lung tissue. The results of the simulations were compared with one another through dose or energy deposition profiles, r 90 calculations, and γ-analyses. RESULTS: Both codes gave very similar results with monoenergetic beams incident on a water phantom. Systematic differences were observed between MC2 and TOPAS simulations when using a lung or bone slab in a water phantom, particularly in the r 90 values, where TOPAS consistently calculated r 90 to be deeper by about 0.4%. When comparing the performance of the 2 codes in a CT geometry, the results were still very similar, exemplified by a 3-dimensional γ-analysis pass rate > 95% at the 2%-2-mm criterion for tissues from both head and neck and lung. CONCLUSION: Differences between TOPAS and MC2 were minor and were not considered clinically relevant.

Fixed- versus Variable-RBE Computations for Intensity Modulated Proton Therapy.

PURPOSE: To evaluate how using models of proton therapy that incorporate variable relative biological effectiveness (RBE) versus the current practice of using a fixed RBE of 1.1 affects dosimetric indices on treatment plans for large cohorts of patients treated with intensity modulated proton therapy (IMPT). METHODS AND MATERIALS: Treatment plans for 4 groups of patients who received IMPT for brain, head-and-neck, thoracic, or prostate cancer were selected. Dose distributions were recalculated in 4 ways: 1 with a fast-dose Monte Carlo calculator with fixed RBE and 3 with RBE calculated to 3 different models-McNamara, Wedenberg, and repair-misrepair-fixation. Differences among dosimetric indices (D02, D50, D98, and mean dose) for target volumes and organs at risk (OARs) on each plan were compared between the fixed-RBE and variable-RBE calculations. RESULTS: In analyses of all target volumes, for which the main concern is underprediction or RBE less than 1.1, none of the models predicted an RBE less than 1.05 for any of the cohorts. For OARs, the 2 models based on linear energy transfer, McNamara and Wedenberg, systematically predicted RBE >1.1 for most structures. For the mean dose of 25% of the plans for 2 OARs, they predict RBE equal to or larger than 1.4, 1.3, 1.3, and 1.2 for brain, head-and-neck, thorax, and prostate, respectively. Systematically lower increases in RBE are predicted by repair-misrepair-fixation, with a few cases (eg, femur) in which the RBE is less than 1.1 for all plans. CONCLUSIONS: The variable-RBE models predict increased doses to various OARs, suggesting that strategies to reduce high-dose linear energy transfer in critical structures should be developed to minimize possible toxicity associated with IMPT.

Nonhomologous End Joining Is More Important Than Proton Linear Energy Transfer in Dictating Cell Death.

PURPOSE: This study seeks to identify biological factors that may yield a therapeutic advantage of proton therapy versus photon therapy. Specifically, we address the role of nonhomologous end-joining (NHEJ) and homologous recombination (HR) in the survival of cells in response to clinical photon and proton beams. METHODS AND MATERIALS: We irradiated HT1080, M059K (DNA-PKcs+/+), and HCC1937 human cancer cell lines and their isogenic counterparts HT1080-shDNA-PKcs, HT1080-shRAD51IND, M059J (DNA-PKcs-/-), and HCC1937-BRCA1 (BRCA1 complemented) to assess cell clonogenic survival and γ-H2AX radiation-induced foci. Cells were irradiated with either clinically relevant photons or 1 of 3 proton linear energy transfer (LET) values. RESULTS: Our results indicate that NHEJ deficiency is more important in dictating cell survival than proton LET. Cells with disrupted HR through BRCA1 mutation showed increased radiosensitivity only for high-LET protons whereas RAD51 depletion showed increased radiosensitivity for both photons and protons. DNA double strand breaks, assessed by γ-H2AX radiation-induced foci, showed greater numbers after 24 hours in cells exposed to higher LET protons. We also observed that NHEJ-deficient cells were unable to repair the vast majority of double strand breaks after 24 hours. CONCLUSIONS: BRCA1 mutation significantly sensitizes cells to protons, but not photons. Loss of NHEJ renders cells hypersensitive to radiation, whereas the relative importance of HR increases with LET across several cell lines. This may be attributable to the more clustered damage induced by higher LET protons, which are harder to repair through NHEJ. This highlights the importance of tumor biology in dictating treatment modality and suggests BRCA1 as a potential biomarker for proton therapy response. Our data also support the use of pharmacologic inhibitors of DNA repair to enhance the sensitivity to different radiation types, although this raises issues for normal tissue toxicity.