Abstract Background and purpose A constant relative biological effectiveness (RBE) is used for clinical proton therapy; however, experimental evidence indicates that RBE can vary. We analyzed ...pediatric ependymoma patients who received proton therapy to determine if areas of normal tissue damage indicated by post-treatment image changes were associated with increased biological dose effectiveness. Material and methods Fourteen of 34 children showed T2-FLAIR hyperintensity on post-treatment magnetic resonance (MR) images. We delineated regions of treatment-related change and calculated dose and linear energy transfer (LET) distributions with Monte Carlo. Voxel-level image change data were fit to a generalized linear model incorporating dose and LET. Cross-validation was used to determine model parameters and for receiver operating characteristic curve analysis. Tolerance dose (TD50 ; dose at which 50% of patients would experience toxicity) was interpolated from the model. Results Image changes showed dependence on increasing LET and dose. TD50 decreased with increasing LET, indicating an increase in biological dose effectiveness. The cross-validated area under the curve for the model was 0.91 (95% confidence interval 0.88–0.94). Conclusions Our correlation of changes on MR images after proton therapy with increased LET constitutes the first clinical evidence of variable proton biological effectiveness.
Three commercial metal artifact reduction methods were evaluated for use in computed tomography (CT) imaging in the presence of clinically realistic metal implants: Philips O-MAR, GE's monochromatic ...gemstone spectral imaging (GSI) using dual-energy CT, and GSI monochromatic imaging with metal artifact reduction software applied (MARs). Each method was evaluated according to CT number accuracy, metal size accuracy, and streak artifact severity reduction by using several phantoms, including three anthropomorphic phantoms containing metal implants (hip prosthesis, dental fillings and spinal fixation rods). All three methods showed varying degrees of success for the hip prosthesis and spinal fixation rod cases, while none were particularly beneficial for dental artifacts. Limitations of the methods were also observed. MARs underestimated the size of metal implants and introduced new artifacts in imaging planes beyond the metal implant when applied to dental artifacts, and both the O-MAR and MARs algorithms induced artifacts for spinal fixation rods in a thoracic phantom. Our findings suggest that all three artifact mitigation methods may benefit patients with metal implants, though they should be used with caution in certain scenarios.
Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid ...critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury.
Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016.
The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning.
Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.
Purpose:
The motivation of this study was to find and eliminate the cause of errors in dose‐averaged linear energy transfer (LET) calculations from therapeutic protons in small targets, such as ...biological cell layers, calculated using the geant 4 Monte Carlo code. Furthermore, the purpose was also to provide a recommendation to select an appropriate LET quantity from geant 4 simulations to correlate with biological effectiveness of therapeutic protons.
Methods:
The authors developed a particle tracking step based strategy to calculate the average LET quantities (track‐averaged LET, LETt and dose‐averaged LET, LETd) using geant 4 for different tracking step size limits. A step size limit refers to the maximally allowable tracking step length. The authors investigated how the tracking step size limit influenced the calculated LETt and LETd of protons with six different step limits ranging from 1 to 500 μm in a water phantom irradiated by a 79.7‐MeV clinical proton beam. In addition, the authors analyzed the detailed stochastic energy deposition information including fluence spectra and dose spectra of the energy‐deposition‐per‐step of protons. As a reference, the authors also calculated the averaged LET and analyzed the LET spectra combining the Monte Carlo method and the deterministic method. Relative biological effectiveness (RBE) calculations were performed to illustrate the impact of different LET calculation methods on the RBE‐weighted dose.
Results:
Simulation results showed that the step limit effect was small for LETt but significant for LETd. This resulted from differences in the energy‐deposition‐per‐step between the fluence spectra and dose spectra at different depths in the phantom. Using the Monte Carlo particle tracking method in geant 4 can result in incorrect LETd calculation results in the dose plateau region for small step limits. The erroneous LETd results can be attributed to the algorithm to determine fluctuations in energy deposition along the tracking step in geant 4. The incorrect LETd values lead to substantial differences in the calculated RBE.
Conclusions:
When the geant 4 particle tracking method is used to calculate the average LET values within targets with a small step limit, such as smaller than 500 μm, the authors recommend the use of LETt in the dose plateau region and LETd around the Bragg peak. For a large step limit, i.e., 500 μm, LETd is recommended along the whole Bragg curve. The transition point depends on beam parameters and can be found by determining the location where the gradient of the ratio of LETd and LETt becomes positive.
We describe the development and analysis of a new teletherapy modality that, through a novel approach to targeted radiation delivery, has the potential to provide greater conformality than ...conventional photon-based treatments. The proposed system uses an X-ray lens to reflect photons from a conventional X-ray tube toward a focal spot. The resulting dose distributions have a highly localized peak dose, with lower doses in the converging radiation cone. Physical principles governing the design of this system are presented, along with a series of measurements analyzing various characteristics of the converging beam. The beam was designed to be nearly monoenergetic (~ 59 keV), with an energy bandwidth of approximately 10 keV allowing for treatment energies lower than conventional therapies. The focal spot was measured to be approximately 2.5 cm long and 4 mm wide. Mounting the proposed X-ray delivery system on a robotic arm would allow sub-millimeter accuracy in focal spot positioning, resulting in highly conformal dose distribution via the optimal placement of individual focal spots within the target volume. Aspects of this novel radiation beam are discussed considering their possible clinical application as a treatment approach that takes maximum advantage of the unique properties afforded by converging X-ray beam therapy.
The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton ...therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE.
Purpose:
The purpose of the work reported here was to investigate the influence of sub‐millimeter size heterogeneities on the degradation of the distal edges of proton beams and to validate Monte ...Carlo (MC) methods’ ability to correctly predict such degradation.
Methods:
A custom‐designed high‐resolution plastic phantom approximating highly heterogeneous, lung‐like structures was employed in measurements and in Monte Carlo simulations to evaluate the degradation of proton Bragg curves penetrating heterogeneous media.
Results:
Significant differences in distal falloff widths and in peak dose values were observed in the measured and the Monte Carlo simulated curves compared to pristine proton Bragg curves. Furthermore, differences between simulations of beams penetrating CT images of the phantom did not agree well with the corresponding experimental differences. The distal falloff widths in CT image‐based geometries were underestimated by up to 0.2 cm in water (corresponding to 0.8–1.4 cm in lung tissue), and the peak dose values of pristine proton beams were overestimated by as much as ˜35% compared to measured curves or depth‐dose curves simulated on the basis of true geometry. The authors demonstrate that these discrepancies were caused by the limited spatial resolution of CT images that served as a basis for dose calculations and lead to underestimation of the impact of the fine structure of tissue heterogeneities. A convolution model was successfully applied to mitigate the underestimation.
Conclusions:
The results of this study justify further development of models to better represent heterogeneity effects in soft‐tissue geometries, such as lung, and to correct systematic underestimation of the degradation of the distal edge of proton doses.
Bcl-xL plays a critical role in maintaining cell survival. However, the relationship between the potential interaction of Bcl-xL with other cytosolic proteins and the regulation of cell survival ...remains incompletely defined. We have identified translationally controlled tumor protein (TCTP), a multifunctional protein, as a novel antiapoptotic Bcl-xL-interacting protein. TCTP interacted in vivo and in vitro with Bcl-xL, and their sites have been mapped to an N-terminal region of TCTP and the Bcl-2 homology domain 3 of Bcl-xL. Consistent with a role in maintaining T-cell survival during activation, TCTP was significantly upregulated in murine T cells activated by T-cell antigen receptor (TCR) ligation and CD28 costimulation, which was correlated with the upregulation of Bcl-xL in activated T cells. Moreover, downregulation of TCTP expression by antisense technology in T cells results in the increase of T-cell apoptosis. Furthermore, the N-terminal region of TCTP was required for its ability to inhibit apoptosis. In conclusion, this study has demonstrated that an N-terminal region of a cytosolic protein, TCTP, is required for its binding to Bcl-xL and for its antiapoptotic activity.
Purpose:
Dose calculation errors near metal implants are caused by limitations of the dose calculation algorithm in modeling tissue/metal interface effects as well as density assignment errors caused ...by imaging artifacts. The purpose of this study was to investigate two strategies for reducing dose calculation errors near metal implants: implementation of metal-based energy deposition kernels in the convolution/superposition (C/S) dose calculation method and use of metal artifact reduction methods for computed tomography (CT) imaging.
Methods:
Both error reduction strategies were investigated using a simple geometric slab phantom with a rectangular metal insert (composed of titanium or Cerrobend), as well as two anthropomorphic phantoms (one with spinal hardware and one with dental fillings), designed to mimic relevant clinical scenarios. To assess the dosimetric impact of metal kernels, the authors implemented titanium and silver kernels in a commercial collapsed cone C/S algorithm. To assess the impact of CT metal artifact reduction methods, the authors performed dose calculations using baseline imaging techniques (uncorrected 120 kVp imaging) and three commercial metal artifact reduction methods: Philips Healthcare’s o-mar, GE Healthcare’s monochromatic gemstone spectral imaging (gsi) using dual-energy CT, and gsi with metal artifact reduction software (mars) applied. For the simple geometric phantom, radiochromic film was used to measure dose upstream and downstream of metal inserts. For the anthropomorphic phantoms, ion chambers and radiochromic film were used to quantify the benefit of the error reduction strategies.
Results:
Metal kernels did not universally improve accuracy but rather resulted in better accuracy upstream of metal implants and decreased accuracy directly downstream. For the clinical cases (spinal hardware and dental fillings), metal kernels had very little impact on the dose calculation accuracy (<1.0%). Of the commercial CT artifact reduction methods investigated, the authors found that o-mar was the most consistent method, resulting in either improved dose calculation accuracy (dental case) or little impact on calculation accuracy (spine case). gsi was unsuccessful at reducing the severe artifacts caused by dental fillings and had very little impact on calculation accuracy. gsi with mars on the other hand gave mixed results, sometimes introducing metal distortion and increasing calculation errors (titanium rectangular implant and titanium spinal hardware) but other times very successfully reducing artifacts (Cerrobend rectangular implant and dental fillings).
Conclusions:
Though successful at improving dose calculation accuracy upstream of metal implants, metal kernels were not found to substantially improve accuracy for clinical cases. Of the commercial artifact reduction methods investigated, o-mar was found to be the most consistent candidate for all-purpose CT simulation imaging. The mars algorithm for gsi should be used with caution for titanium implants, larger implants, and implants located near heterogeneities as it can distort the size and shape of implants and increase calculation errors.
Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or ...for large retrospective studies. Track-repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 μs.
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