Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Automation of Monte Carlo-based treatment plan verification for proton therapy.

PURPOSE: Independent calculations of proton therapy plans are an important quality control procedure in treatment planning. When using custom Monte Carlo (MC) models of the beamline, deploying the calculations can be laborious, time consuming, and require in-depth knowledge of the computational environment. We developed an automated framework to remove these barriers and integrate our MC model into the clinical workflow. MATERIALS AND METHODS: The Eclipse Scripting Application Programming Interface was used to initiate the automation process. A series of MATLAB scripts were then used for preprocessing of input data and postprocessing of results. Additional scripts were used to monitor the calculation process and appropriately deploy calculations to an institutional high-performance computing facility. The automated framework and beamline models were validated against 160 patient specific QA measurements from an ionization chamber array and using a ±3%/3 mm gamma criteria. RESULTS: The automation reduced the human-hours required to initiate and run a calculation to 1-2 min without leaving the treatment planning system environment. Validation comparisons had an average passing rate of 99.4% and were performed at depths ranging from 1 to 15 cm. CONCLUSION: An automated framework for running MC calculations was developed which enables the calculation of dose and linear energy transfer within a clinically relevant workflow and timeline. The models and framework were validated against patient specific QA measurements and exhibited excellent agreement. Before this implementation, execution was prohibitively complex for an untrained individual and its use restricted to a research environment.

Systemic mechanisms and effects of ionizing radiation: A new 'old' paradigm of how the bystanders and distant can become the players.

Exposure of cells to any form of ionizing radiation (IR) is expected to induce a variety of DNA lesions, including double strand breaks (DSBs), single strand breaks (SSBs) and oxidized bases, as well as loss of bases, i.e., abasic sites. The damaging potential of IR is primarily related to the generation of electrons, which through their interaction with water produce free radicals. In their turn, free radicals attack DNA, proteins and lipids. Damage is induced also through direct deposition of energy. These types of IR interactions with biological materials are collectively called 'targeted effects', since they refer only to the irradiated cells. Earlier and sometimes 'anecdotal' findings were pointing to the possibility of IR actions unrelated to the irradiated cells or area, i.e., a type of systemic response with unknown mechanistic basis. Over the last years, significant experimental evidence has accumulated, showing a variety of radiation effects for 'out-of-field' areas (non-targeted effects-NTE). The NTE involve the release of chemical and biological mediators from the 'in-field' area and thus the communication of the radiation insult via the so called 'danger' signals. The NTE can be separated in two major groups: bystander and distant (systemic). In this review, we have collected a detailed list of proteins implicated in either bystander or systemic effects, including the clinically relevant abscopal phenomenon, using improved text-mining and bioinformatics tools from the literature. We have identified which of these genes belong to the DNA damage response and repair pathway (DDR/R) and made protein-protein interaction (PPi) networks. Our analysis supports that the apoptosis, TLR-like and NOD-like receptor signaling pathways are the main pathways participating in NTE. Based on this analysis, we formulate a biophysical hypothesis for the regulation of NTE, based on DNA damage and apoptosis gradients between the irradiation point and various distances corresponding to bystander (5mm) or distant effects (5cm). Last but not least, in order to provide a more realistic support for our model, we calculate the expected DSB and non-DSB clusters along the central axis of a representative 200.6MeV pencil beam calculated using Monte Carlo DNA damage simulation software (MCDS) based on the actual beam energy-to-depth curves used in therapy.

A semi-empirical model for the therapeutic range shift estimation caused by inhomogeneities in proton beam therapy.

The purpose of this study was to devise a simple semi-empirical model to estimate the range shift in clinical practices with high-Z inhomogeneity in proton beam. A semi-empirical model utilizing the logarithmic dependence on Z in stopping power from Bohr's classical approach has been developed to calculate the range shift due to the presence of inhomogeneity. Range shift from metallic plates of atomic number Z of various thicknesses were measured in water using a parallel plate ionization chamber and calculated with the FLUKA Monte Carlo code. The proton range shifts for bone and polymethyl methacrylate (PMMA) were estimated using the semi-empirical model and compared with Monte Carlo calculation. The semi-empirical equation to determine range shift and water equivalent thickness is presented. The model predicts a shift of the therapeutic range to within 2.5% accuracy for initial proton energies of 50 to 250 MeV and atomic numbers from 3.3 (effective Z for water) to 82. This equation is independent of beam energy, and thus provides range shift from high-Z materials without the knowledge of proton energy. The proposed method of calculating the therapeutic range shift accurately requires only knowledge of the effective or actual atomic number of the inhomogeneity and the thickness of the inhomogeneity along the beam direction. The model generalizes the range shift calculation for any material based on its effective atomic number, and permits reliable prediction of the range shift for material combinations where no data is currently available. The proposed model can be readily implemented in routine clinical practice for proton range shift estimation and quality assurance on the treatment planning.

Three-dimensional dose and LETD prediction in proton therapy using artificial neural networks.

PURPOSE: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning (KBP) is a domain that may help to address all three. METHODS: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LETD ) distributions. The data set was split into training (n = 82), validation (n = 17), and test (n = 18) sets. Model performance was evaluated on the test set using dose- and LETD -volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. RESULTS: Dose-volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose-volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD -volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0 keV/µm for L0.1cc to brainstem. CONCLUSIONS: We have devised the first three-dimensional dose and LETD -prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy.

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

PURPOSE: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. METHODS AND MATERIALS: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. RESULTS: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. CONCLUSIONS: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Pitfalls of tungsten multileaf collimator in proton beam therapy.

PURPOSE: Particle beam therapy is associated with significant startup and operational cost. Multileaf collimator (MLC) provides an attractive option to improve the efficiency and reduce the treatment cost. A direct transfer of the MLC technology from external beam radiation therapy is intuitively straightforward to proton therapy. However, activation, neutron production, and the associated secondary cancer risk in proton beam should be an important consideration which is evaluated. METHODS: Monte Carlo simulation with FLUKA particle transport code was applied in this study for a number of treatment models. The authors have performed a detailed study of the neutron generation, ambient dose equivalent [H∗(10)], and activation of a typical tungsten MLC and compared with those obtained from a brass aperture used in a typical proton therapy system. Brass aperture and tungsten MLC were modeled by absorber blocks in this study, representing worst-case scenario of a fully closed collimator. RESULTS: With a tungsten MLC, the secondary neutron dose to the patient is at least 1.5 times higher than that from a brass aperture. The H∗(10) from a tungsten MLC at 10 cm downstream is about 22.3 mSv/Gy delivered to water phantom by noncollimated 200 MeV beam of 20 cm diameter compared to 14 mSv/Gy for the brass aperture. For a 30-fraction treatment course, the activity per unit volume in brass aperture reaches 5.3 × 104 Bq cm(-3) at the end of the last treatment. The activity in brass decreases by a factor of 380 after 24 h, additional 6.2 times after 40 days of cooling, and is reduced to background level after 1 yr. Initial activity in tungsten after 30 days of treating 30 patients per day is about 3.4 times higher than in brass that decreases only by a factor of 2 after 40 days and accumulates to 1.2 × 106 Bq cm(-3) after a full year of operation. The daily utilization of the MLC leads to buildup of activity with time. The overall activity continues to increase due to (179)Ta with a half-life of 1.82 yr and thus require prolonged storage for activity cooling. The H∗(10) near the patient side of the tungsten block is about 100 µSv/h and is 27 times higher at the upstream side of the block. This would lead to an accumulated dose for therapists in a year that may exceed occupational maximum permissible dose (50 mSv/yr). The value of H∗(10) at the upstream surface of the tungsten block is about 220 times higher than that of the brass. CONCLUSIONS: MLC is an efficient way for beam shaping and overall cost reduction device in proton therapy. However, based on this study, tungsten seems to be not an optimal material for MLC in proton beam therapy. Usage of tungsten MLC in clinic may create unnecessary risks associated with the secondary neutrons and induced radioactivity for patients and staff depending on the patient load. A careful selection of material for manufacturing of an optimal MLC for proton therapy is thus desired.

Monte Carlo framework for commissioning a synchrotron-based discrete spot scanning proton beam system and treatment plan verification.

This study aimed to develop a Monte Carlo (MC) framework for commissioning the narrow proton beams (spot size sigma, 5.2 mm 2 mm at isocenter for 69.4 MeV-221.3 MeV for the main beam option and 4.1 mm 1.3 mm for the minibeam option respectively) of a synchrotron-based proton therapy system and design an independent absolute dose calculation engine for intensity-modulated proton treatments. A proton therapy system (Hitachi PROBEAT-V) was simulated using divergent and convergent beam models at the nozzle entrance. The innovative source weighting scheme for the MC simulation with TOPAS (TOol for PArticle Simulations) was implemented using dose output data for the absolute dose calculations. The results of the MC simulation were compared to the experimental data, analyzed and used to commission the treatment planning system. Two MC models, divergent and convergent beams were implemented. The convergent beam model produced a high level of agreement when MC and measurements were analyzed. The beam ellipticity did not result in significant differences between MC simulated and treatment planning system calculated doses. A model of a synchrotron-based spot scanning proton therapy system has been developed and implemented in the TOPAS MC transport code framework. The dose computation engine is useful for treatment plan verification with primary and minibeam beam option.

Proton therapy delivery method affects dose-averaged linear energy transfer in patients.

The dosimetric advantages of proton therapy have led to its rapid proliferation in recent decades. This has been accompanied by a shift in technology from older units that deliver protons by passive scattering (PS) to newer units that increasingly use pencil-beam scanning (PBS). The biologic effectiveness of proton physical dose purportedly rises with increasing dose-weighted average linear energy transfer (LETD). The objective of this study was to determine the extent to which proton delivery methods affect LETD. We calculated LETDfrom simple, dosimetrically matched, and clinical treatment plans with TOPAS Monte-Carlo transport code. Simple treatment plans comprised single fields of PS and PBS protons in a water phantom. We performed simulations of matched and clinical treatment plans by using the treatment and anatomic data obtained from a cohort of children with craniopharyngioma who previously received PS or PBS proton therapy. We compared the distributions of LETDfrom PS and PBS delivery methods in clinically relevant ROIs. Wilcoxon signed-rank tests comparing single fields in water revealed that the LETDvalues from PBS were significantly greater than those from PS inside and outside the targeted volume (p < 0.01). Statistical tests comparing LETD-volume histograms from matched and clinical treatment plans showed that LETDwas generally greater for PBS treatment plans than for PS treatment plans (p < 0.05). In conclusion, the proton delivery method affects LETDboth inside and outside of the target volume. These findings suggest that PBS is more biologically effective than PS. Given the rapid expansion of PBS proton therapy, future studies are needed to confirm the applicability of treatment evaluation methods developed for PS proton therapy to those for modern PBS treatments to ensure their safety and effectiveness for the growing population of patients receiving proton therapy. This study uses data from two clinical trials: NCT01419067 and NCT02792582.

Dose perturbation caused by metallic port in breast tissue expander in proton beam therapy.

Proton beam treatment is being looked favourably now in breast treatment. Tissue expanders are often placed after mastectomy that contains metallic port for saline injection which produces dose perturbations in proton beam therapy with uncertain dosimetry. Dose perturbation for a stainless-steel injection port from a breast implant is investigated in this study. Measurements, Monte-Carlo simulation, and calculated dose distribution of plans based on kVCT and MVCT images are compared. Treatment plans are performed on kVCT and MVCT images to observe the effect of metal artifact from the breast implant. The kVCT based plan underestimates the beam range due to the overestimated water equivalent thickness of the metal ports as a result of image degradation. Compared to the measurement with metal port in the proton beam, the MVCT-based treatment planning provides more accurate dose calculation than the kVCT-based results. The dose perturbation factor calculated from MVCT planning is within 10% of the measurement results while HU corrected kVCT plan still shows dose difference as large as 100% due to the incorrect range pull back calculation caused by the misrepresentation of the volume between the plastic cap and the stainless-steel base. The dose enhancement observed at the metal and solid water interface is as large as 15%, which needs to be accounted for in the planning process if there is a clinical concern. Dose reduction as large as 16% is observed with depth from 1 cm to 4 cm underneath the thickest part of the metallic port whereas lateral dose perturbation is also seen up to 7 mm. The measurement data are supported by the Monte-Carlo simulated results with a maximum dose difference of 6%. It is concluded that if proton beam is used with metallic port, MVCT imaging data is recommended. In lieu of MVCT, DECT, CT scanner with metal artifact reduction software or in the very least, extended HU range should be used to reduce the streaking artifact as well as to produce a more accurate image of the metallic port.

Technical Note: Design and characterization of a large diameter parallel plate ionization chamber for accurate integral depth dose measurements with proton beams.

PURPOSE: The goal was to develop and test a large diameter parallel plate ionization chamber capable of intercepting at least 98% of the proton beamlets tested with the system. METHODS: A commercial synchrotron proton therapy system was used for the study (Hitachi, Ltd, Hitachi City, Japan; Model: Probeat-V). The energies investigated were in the range of 100 to 192 MeV. Three beam spot options available from the system were used. A PTW Bragg peak IC of diameter 84 mm (BP84) (Model PTW34070) was employed for comparison in a scanning water phantom. A prototype of 150 mm diameter was produced (PTW, Freiburg, Germany; model: T34089) and used for the testing. Monte Carlo calculations were also performed with FLUKA to guide the BP150 design and for comparison to the radiological measurements. For comparison, a 40 cm diameter ideal virtual detector was included in the Monte Carlo model. RESULTS: The measured proton range R90 agrees between the BP84 and BP150 ionization chambers within +0.06/-0.27 mm across the energies 100-192 MeV, which is less than the daily experimental setup uncertainty of 0.4 mm. The differences in the absolute integral depth dose curves (IDDs) between the BP84 and BP150 ranged from 0.3% to 1.0% for the spot sizes and beam energies tested. As predicted by the Monte Carlo modeling, the greatest differences were found in the plateau region of the IDDs. Also, the IDDs measured with the BP150 were very similar to those of the ideal 40 cm diameter detector Monte Carlo simulations. CONCLUSIONS: We conclude that the BP150 offers a small, but a useful reduction in uncertainty from the nuclear halo effect for the system under test.

Challenges of dosimetry of ultra-short pulsed very high energy electron beams.

Very high energy electrons (VHEE) in the range from 100 to 250MeV have the potential of becoming an alternative modality in radiotherapy because of their improved dosimetric properties compared with 6-20MV photons generated by clinical linear accelerators (LINACs). VHEE beams have characteristics unlike any other beams currently used for radiotherapy: femtosecond to picosecond duration electron bunches, which leads to very high dose per pulse, and energies that exceed that currently used in clinical applications. Dosimetry with conventional online detectors, such as ionization chambers or diodes, is a challenge due to non-negligible ion recombination effects taking place in the sensitive volumes of these detectors. FLUKA and Geant4 Monte Carlo (MC) codes have been employed to study the temporal and spectral evolution of ultrashort VHEE beams in a water phantom. These results are complemented by ion recombination measurements employing an IBA CC04 ionization chamber for a 165MeV VHEE beam. For comparison, ion recombination has also been measured using the same chamber with a conventional 20MeV electron beam. This work demonstrates that the IBA CC04 ionization chamber exhibits significant ion recombination and is therefore not suitable for dosimetry of ultrashort pulsed VHEE beams applying conventional correction factors. Further study is required to investigate the applicability of ion chambers in VHEE dosimetry.

Evaluation of underdosage in the external photon beam radiotherapy of glottic carcinoma: Monte Carlo study.

PURPOSE: Underdosage in the human larynx may be the true factor behind the decrease in local control rates. PATIENTS AND METHODS: To evaluate underdosage with Monte Carlo a CT-based geometrical model of the patient's neck (mathematical neck) was created. Dose was calculated for a pair of 6 Me V parallel-opposed photon beams modulated with 15 degree steel wedges. RESULTS: At least 5% of volume of 3.5 cm(3) hypothetical tumor near the air wall of the larynx receives less than 86% of the maximum tumor dose. The same volume received less than 91% of the maximum tumor dose when the mathematical neck had no air cavities. CONCLUSIONS: We conclude the significant underdosage at the air-tissue interface in the larynx occurs in traditional radiotherapy treatments, especially in the glottic part of the larynx.

Feasibility of RACT for 3D dose measurement and range verification in a water phantom.

PURPOSE: The objective of this study is to establish the feasibility of using radiation-induced acoustics to measure the range and Bragg peak dose from a pulsed proton beam. Simulation studies implementing a prototype scanner design based on computed tomographic methods were performed to investigate the sensitivity to proton range and integral dose. METHODS: Derived from thermodynamic wave equation, the pressure signals generated from the dose deposited from a pulsed proton beam with a 1 cm lateral beam width and a range of 16, 20, and 27 cm in water using Monte Carlo methods were simulated. The resulting dosimetric images were reconstructed implementing a 3D filtered backprojection algorithm and the pressure signals acquired from a 71-transducer array with a cylindrical geometry (30 × 40 cm) rotated over 2π about its central axis. Dependencies on the detector bandwidth and proton beam pulse width were performed, after which, different noise levels were added to the detector signals (using 1 µs pulse width and a 0.5 MHz cutoff frequency/hydrophone) to investigate the statistical and systematic errors in the proton range (at 20 cm) and Bragg peak dose (of 1 cGy). RESULTS: The reconstructed radioacoustic computed tomographic image intensity was shown to be linearly correlated to the dose within the Bragg peak. And, based on noise dependent studies, a detector sensitivity of 38 mPa was necessary to determine the proton range to within 1.0 mm (full-width at half-maximum) (systematic error < 150 µm) for a 1 cGy Bragg peak dose, where the integral dose within the Bragg peak was measured to within 2%. For existing hydrophone detector sensitivities, a Bragg peak dose of 1.6 cGy is possible. CONCLUSIONS: This study demonstrates that computed tomographic scanner based on ionizing radiation-induced acoustics can be used to verify dose distribution and proton range with centi-Gray sensitivity. Realizing this technology into the clinic has the potential to significantly impact beam commissioning, treatment verification during particle beam therapy and image guided techniques.

Effect of Scanning Beam for Superficial Dose in Proton Therapy.

Proton beam delivery technology is under development to minimize the scanning spot size for uniform dose to target, but it is also known that the superficial dose could be as high as the dose at Bragg peak for narrow and small proton beams. The objective of this study is to explore the characteristics of dose distribution at shallow depths using Monte Carlo simulation with the FLUKA code for uniform scanning (US) and discrete spot scanning (DSS) proton beams. The results show that the superficial dose for DSS is relatively high compared to US. Additionally, DSS delivers a highly heterogeneous dose to the irradiated surface for comparable doses at Bragg peak. Our simulation shows that the superficial dose can become as high as the Bragg peak when the diameter of the proton beam is reduced. This may compromise the advantage of proton beam therapy for sparing normal tissue, making skin dose a limiting factor for the clinical use of DSS. Finally, the clinical advantage of DSS may not be essential for treating uniform dose across a large target, as in craniospinal irradiation (CSI).

Proton Therapy Facility Planning From a Clinical and Operational Model.

This paper provides a model for planning a new proton therapy center based on clinical data, referral pattern, beam utilization and technical considerations. The patient-specific data for the depth of targets from skin in each beam angle were reviewed at our center providing megavoltage photon external beam and proton beam therapy respectively. Further, data on insurance providers, disease sites, treatment depths, snout size and the beam angle utilization from the patients treated at our proton facility were collected and analyzed for their utilization and their impact on the facility cost. The most common disease sites treated at our center are head and neck, brain, sarcoma and pediatric malignancies. From this analysis, it is shown that the tumor depth from skin surface has a bimodal distribution (peak at 12 and 26 cm) that has significant impact on the maximum proton energy, requiring the energy in the range of 130-230 MeV. The choice of beam angles also showed a distinct pattern: mainly at 90° and 270°; this indicates that the number of gantries may be minimized. Snout usage data showed that 70% of the patients are treated with 10 cm snouts. The cost of proton beam therapy depends largely on the type of machine, maximum beam energy and the choice of gantry versus fixed beam line. Our study indicates that for a 4-room center, only two gantry rooms could be needed at the present pattern of the patient cohorts, thus significantly reducing the initial capital cost. In the USA, 95% and 100% of patients can be treated with 200 and 230 MeV proton beam respectively. Use of multi-leaf collimators and pencil beam scanning may further reduce the operational cost of the facility.