•FLASH radiation dose-rates consume all the local tissue O2 to form reactive organic hydroperoxides.•Fenton type reactions will be limited in normal vs. cancer tissues due to lower levels of labile ...Fe.•Normal tissues are expected to remove organic hydroperoxides more effectively relative to tumor tissues.•Since tumor tissue cannot remove hydroperoxides as effectively, FLASH and conventional dose rate irradiation are more isoefficient at killing tumor cells compared to normal cells.
For decades the field of radiation oncology has sought to improve the therapeutic ratio through innovations in physics, chemistry, and biology. To date, technological advancements in image guided beam delivery techniques have provided clinicians with their best options for improving this critical tool in cancer care. Medical physics has focused on the preferential targeting of tumors while minimizing the collateral dose to the surrounding normal tissues, yielding only incremental progress. However, recent developments involving ultra-high dose rate irradiation termed FLASH radiotherapy (FLASH-RT), that were initiated nearly 50 years ago, have stimulated a renaissance in the field of radiotherapy, long awaiting a breakthrough modality able to enhance therapeutic responses and limit normal tissue injury. Compared to conventional dose rates used clinically (0.1–0.2 Gy/s), FLASH can implement dose rates of electrons or X-rays in excess of 100 Gy/s. The implications of this ultra-fast delivery of dose are significant and need to be re-evaluated to appreciate the fundamental aspects underlying this seemingly unique radiobiology. The capability of FLASH to significantly spare normal tissue complications in multiple animal models, when compared to conventional rates of dose-delivery, while maintaining persistent growth inhibition of select tumor models has generated considerable excitement, as well as skepticism. Based on fundamental principles of radiation physics, radio-chemistry, and tumor vs. normal cell redox metabolism, this article presents a series of testable, biologically relevant hypotheses, which may help rationalize the differential effects of FLASH irradiation observed between normal tissue and tumors.
The advent of energy-specific collimation in pencil beam scanning (PBS) proton therapy has led to an improved lateral dose conformity for a variety of treatment sites, resulting in better healthy ...tissue sparing. Arc PBS delivery has also been proposed to enhance high-dose conformity about the intended target, reduce skin toxicity, and improve plan robustness. The goal of this work was to determine if the combination of proton arc and energy-specific collimation can generate better dose distributions as a logical next step to maximize the dosimetric advantages of proton therapy. Plans were optimized using a novel DyNamically collimated proton Arc (DNA) genetic optimization algorithm that was designed specifically for the application of proton arc therapy. A treatment planning comparison study was performed by generating an uncollimated two-field intensity modulated proton therapy and partial arc treatments and then replanning these treatments using energy-specific collimation as delivered by a dynamic collimation system, which is a novel collimation technology for PBS. As such, we refer to this novel treatment paradigm as Dynamically Collimated Proton Arc Therapy (DC-PAT). Arc deliveries achieved a superior target conformity and improved organ at risk (OAR) sparing relative to their two-field counterparts at the cost of an increase to the low-dose, high-volume region of the healthy brain. The incorporation of DC-PAT using the DNA optimizer was shown to further improve the tumor dose conformity. When compared to the uncollimated proton arc treatments, the mean dose to the 10mm of surrounding healthy tissue was reduced by 11.4% with the addition of collimation without meaningfully affecting the maximum skin dose (less than 1% change) relative to a multi-field treatment. In this case study, DC-PAT could better spare specific OARs while maintaining better target coverage compared to uncollimated proton arc treatments. While this work presents a proof-of-concept integration of two emerging technologies, the results are promising and suggest that the addition of these two techniques can lead to superior treatment plans warranting further development.
Purpose:
In the absence of a collimation system the lateral penumbra of spot scanning (SS) dose distributions delivered by low energy proton beams is highly dependent on the spot size. For current ...commercial equipment, spot size increases with decreasing proton energy thereby reducing the benefit of the SS technique. This paper presents a dynamic collimation system (DCS) for sharpening the lateral penumbra of proton therapy dose distributions delivered by SS.
Methods:
The collimation system presented here exploits the property that a proton pencil beam used for SS requires collimation only when it is near the target edge, enabling the use of trimmers that are in motion at times when the pencil beam is away from the target edge. The device consists of two pairs of parallel nickel trimmer blades of 2 cm thickness and dimensions of 2 cm × 18 cm in the beamˈs eye view. The two pairs of trimmer blades are rotated 90° relative to each other to form a rectangular shape. Each trimmer blade is capable of rapid motion in the direction perpendicular to the central beam axis by means of a linear motor, with maximum velocity and acceleration of 2.5 m/s and 19.6 m/s2, respectively. The blades travel on curved tracks to match the divergence of the proton source. An algorithm for selecting blade positions is developed to minimize the dose delivered outside of the target, and treatment plans are created both with and without the DCS.
Results:
The snout of the DCS has outer dimensions of 22.6 × 22.6 cm2 and is capable of delivering a minimum treatment field size of 15 × 15 cm2. Using currently available components, the constructed system would weigh less than 20 kg. For irregularly shaped fields, the use of the DCS reduces the mean dose outside of a 2D target of 46.6 cm2 by approximately 40% as compared to an identical plan without collimation. The use of the DCS increased treatment time by 1–3 s per energy layer.
Conclusions:
The spread of the lateral penumbra of low‐energy SS proton treatments may be greatly reduced with the use of this system at the cost of only a small penalty in delivery time.
Dose point kernels for 2,174 radionuclides Graves, Stephen A.; Flynn, Ryan T.; Hyer, Daniel E.
Medical physics (Lancaster),
November 2019, Letnik:
46, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Purpose
Rapid adoption of targeted radionuclide therapy as an oncologic intervention has motivated the development of patient‐specific voxel‐wise approaches to radiation dosimetry. These approaches ...often rely on pretabulated dose point kernels for convolution‐based calculations; however, these dose kernels are sparse in literature and often have suboptimal characteristics. The purpose of this work was to generate an extensive library of dose point kernels with sufficient size and resolution for general clinical application of voxel‐wise dosimetry.
Methods
Nuclear data were acquired for 2174 radionuclides from the National Nuclear Data Center (Brookhaven National Laboratory, accessed March 2018). Based on these data, isotropic point sources of radioactivity in water were simulated using Monte Carlo N‐Particle transport v6.2 (MCNP6.2, Los Alamos National Laboratory). Simulations were separated by emission type for each radionuclide — photons (γ‐rays, x rays), beta particles (positrons, electrons); and discrete electrons (conversion electrons, Auger electrons, Coster–Kronig electrons). Dose was tallied in concentric spherical shells about the point source using an energy deposition pulse‐height tally (MCNP *F8 tally). Bins were spaced every 0.1 mm until a radius of 10 cm, and every 1 mm until a radius of 2 m. Positron emissions where treated as electrons for transport, with annihilation photons generated at the origin within the photon simulation. Alpha particle emissions were not simulated since their energy is deposited within ~0.2 mm of the source. Neutron and spallation effects were not considered. A subset of the resultant dose point kernels (11C, 18F, 32P, 52gMn, 64Cu, 67Ga, 89Sr, 89Zr, 90Y, 99mTc, 111In, 117mSn, 123I, 124I, 125I, 131I, 153Sm, 177Lu, 186Re, 188Re, 211As, 212Pb, 213Bi, 223Ra, and 225Ac) were evaluated for accuracy based on conservation of energy, comparison to kernels in the literature, and statistical precision.
Results
Among dose point kernels that were manually reviewed, good agreement with previously published dose point kernels was observed. Energy within the kernels was found to be conserved to within 1% of the value expected from nuclear data, suggesting that a radius of 2 m was sufficient to capture the almost all of the energy released during decay for all isotopes considered. Local dosimetric uncertainty, evaluated at the radius of 99% energy deposition, was found to be less than 9% for all radioisotopes evaluated. Rebinning data more coarsely by a factor of 10, similar to what would be done for a clinical dose calculation, results in all evaluated kernels having a relative error of less than 1.1% at R50%, 1.5% at R90%, and 2.7% at R99% (the radius corresponding to 50%, 90%, and 99% of total energy deposition, respectively). The kernels produced in this work have been made freely available (https://zenodo.org/record/2564036).
Conclusions
An extensive library of high‐resolution radial dose kernels was generated and validated against published data. In addition to enabling patient‐specific voxel‐wise internal dosimetry by convolution superposition, the generated dose point kernels data may prove useful to the wider health physics community.
To systematically review scientific literature on the use of intensity-modulated brachytherapy (IMBT), including static and dynamic shielding approaches, to enhance therapeutic ratio. Studies were ...evaluated for technique, disease site, dosimetry, applicators, dosimetric calculations, and planning algorithms. Comparisons with standard-of-care brachytherapy techniques, alternative IMBT methods, or both were performed for dose-to-target volumes, organs at risk (OARs), and treatment planning or delivery times.
Inclusion criteria were any peer-reviewed journal articles on IMBT published from January 1, 1980, to January 1, 2019, on PubMed, Google Scholar, Cochrane Library, and EBSCO databases. Two independent investigators reviewed each article for inclusion and exclusion criteria and scope. Data collected on each study included technique, source or shield material, disease site, n of study (n = number of simulated plans/treated patients), dose-to-target/OARs, and planning or delivery times. This review adhered to the Preferred Reporting Items for Systemic reviews and Meta Analyses (PRISMA).
Database queries yielded 1734 results, which were reduced to 436 after exclusion criteria and 78 peer-reviewed journal articles after evaluation of scope. Studies per disease site were 31 for cervical; 16 for rectal; 10 for oculocutaneous; 7 for breast; 6 for prostate; and 8 for other, multiple, or no specific disease site. Eighteen studies demonstrated a significant decrease in dose to OARs (5.1%-68.2%), 11 improved treatment planning or delivery times (7.6%-99.7%), and 6 increased target coverage (18.6%-71.6%) relative to standard-of-care or alternative IMBT technique. IMBT consistently decreased dose to OAR compared with the standard of care at the cost of increased planning or delivery times. Innovations in dose calculation or planning algorithms and applicators were capable of ameliorating prolonged treatment intervals.
IMBT techniques improved the therapeutic ratio by reducing OAR doses, facilitating dose escalation, or both. Static-shielding techniques are clinically available as a result of the advent of commercially available heterogeneity-corrected dose-calculation algorithms, whereas dynamic-shielding techniques are still preclinical.
Abstract
Background
Multiple approaches are under development for delivering temporary intensity modulated brachytherapy (IMBT) using partially shielded applicators wherein the delivered dose ...distributions are sensitive to spatial uncertainties in both the applicator position and shield orientation, rather than only applicator position as with conventional high‐dose‐rate brachytherapy (HDR‐BT). Sensitivity analyses to spatial uncertainties have been reported as components of publications on these emerging technologies, however, a generalized framework for the rigorous determination of the spatial uncertainty tolerances of dose‐volume parameters is needed.
Purpose
To derive and present the population percentile allowance (PPA) method, a generalized mathematical and statistical framework to evaluate the tolerance of temporary IMBT approaches to spatial uncertainties in applicator position and shield orientation.
Methods
A mathematical formalism describing geometric applicator position and shield orientation shifts was derived that supports straight and curved applicators and applies to serial and helical rotating shield brachytherapy (RSBT) and direction modulated brachytherapy (DMBT). The PPA method entails defining the percentage of a patient population receiving a given therapy that is, allowed to receive dose‐volume errors in the target volume and specified organs at risk of a defined percentage or less, then determining what combinations of applicator position and shield orientation systematic errors would be expected to produce that outcome in the population. The PPA method was applied to the use case of multi‐shield helical
169
Yb‐based RSBT for cervical cancer, with 45° and 180° shield emission angles. A total of 37 cervical cancer patients were considered in the population, with average (± 1 standard deviation) HR‐CTV volumes of 79 cm
3
± 37 cm
3
and optimized baseline treatment plans (no spatial uncertainties applied) created for each patient to meet dose‐volume requirements of 85 Gy
EQD2
(equivalent uniform dose in 2 Gy fraction), with
D
2cc
tolerance doses of 90 Gy
EQD2
, 75 Gy
EQD2
, and 75 Gy
EQD2
for bladder, rectum, and sigmoid colon, respectively.
Results
For the PPA requirement that 90% of cervical cancer patients receiving multi‐shield helical RSBT could have a maximum dose‐volume uncertainty of 10% for high‐risk clinical target volume (HR‐CTV)
D
90
(minimum dose to hottest 90%) and bladder, rectum, and sigmoid colon
D
2cc
(minimum dose to hottest 2 cm
3
), the tolerance systematic applicator position and shield orientation uncertainties were approximately ± 1.0 mm and ± 4.25°, respectively. For ± 1.5 mm and ± 5° systematic applicator position and shield orientation tolerances, 90% of the patients considered would have a maximum dose‐volume uncertainty of 12.8% or less.
Conclusion
The PPA method was formalized to determine the temporary IMBT spatial uncertainty tolerances that would be expected to result in an allowed percentage of a population of patients receiving relative dose‐volume errors above a defined percentage. Multi‐shield, helical
169
Yb‐based RSBT for cervical cancer was evaluated and tolerances determined, which, if applied on each treatment fraction, would represent an extreme situation. The PPA method is applicable to a variety of temporary IMBT approaches and can be used to rigorously determine the design parameters for the delivery systems such as mechanical driver motor accuracy, shield angle backlash, applicator rotation, and applicator fixation stability.
Background
Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost‐effective 169Yb production method. 169Yb is a traditionally ...expensive isotope suitable for this purpose, with an average γ‐ray energy of 93 keV. Re‐activating a single 169Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single‐activation sources. With re‐activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via 168Yb burnup and 169Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re‐activation.
Purpose
To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the 169Yb production process, with and without re‐activation.
Methods and Materials
A time‐dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub‐volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm3, at thermal neutron fluxes from 1 × 1014 to 1 × 1015 n cm−2 s−1. The 168Yb‐Yb2O3 density was 8.5 g cm−3 with 82% 168Yb‐enrichment. As an example, a reference re‐activatable 169Yb active source (RRS) constructed of 82%‐enriched 168Yb‐Yb2O3 precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm3 volume, 8.5 g cm−3 density, and a thermal neutron activation flux of 4 × 1014 neutrons cm‐2 s‐1.
Results
The average clinical 169Yb activity for a 0.99 versus 0.31 mm3 source dropped from 20.1 to 7.5 Ci for a 4 × 1014 n cm‐2 s‐1 activation flux and from 20.9 to 8.7 Ci for a 1 × 1015 n cm‐2 s‐1 activation flux. For thermal neutron fluxes ≥2 × 1014 n cm‐2 s‐1, total precursor and reactor time per clinic‐year were maximized at a source volume of 0.99 mm3 and reached a near minimum at 3 mm3. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic‐year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects.
Conclusions
Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic‐year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical 169Yb activity decreased substantially below 20 Ci for source volumes under 1 mm3. Increasing source volume above 3 mm3 adds little value in precursor and reactor time savings and has a geometric disadvantage.
Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost-effective
Yb production method.
Yb is a traditionally expensive ...isotope suitable for this purpose, with an average γ-ray energy of 93 keV. Re-activating a single
Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single-activation sources. With re-activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via
Yb burnup and
Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re-activation.
To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the
Yb production process, with and without re-activation.
A time-dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub-volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm
, at thermal neutron fluxes from 1 × 10
to 1 × 10
n cm
s
. The
Yb-Yb
O
density was 8.5 g cm
with 82%
Yb-enrichment. As an example, a reference re-activatable
Yb active source (RRS) constructed of 82%-enriched
Yb-Yb
O
precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm
volume, 8.5 g cm
density, and a thermal neutron activation flux of 4 × 10
neutrons cm
s
.
The average clinical
Yb activity for a 0.99 versus 0.31 mm
source dropped from 20.1 to 7.5 Ci for a 4 × 10
n cm
s
activation flux and from 20.9 to 8.7 Ci for a 1 × 10
n cm
s
activation flux. For thermal neutron fluxes ≥2 × 10
n cm
s
, total precursor and reactor time per clinic-year were maximized at a source volume of 0.99 mm
and reached a near minimum at 3 mm
. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic-year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects.
Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic-year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical
Yb activity decreased substantially below 20 Ci for source volumes under 1 mm
. Increasing source volume above 3 mm
adds little value in precursor and reactor time savings and has a geometric disadvantage.
Accurate beam modeling is essential to help ensure overall accuracy in the radiotherapy process. This study describes our experience with beam model validation of a Monaco treatment planning system ...on a Versa HD linear accelerator. Data were collected such that Monaco beam models could be generated using three algorithms: collapsed cone (CC) and photon Monte Carlo (MC) for photon beams, and electron Monte Carlo (eMC) for electron beams. Validations are performed on measured percent depth doses (PDDs) and profiles, for open‐field point‐doses in homogenous and heterogeneous media, and for obliquely incident electron beams. Gamma analysis is used to assess the agreement between calculation and measurement for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans, including volumetric modulated arc therapy for stereotactic body radiation therapy (VMAT SBRT). For all relevant conditions, gamma index values below 1 are obtained when comparing Monaco calculated PDDs and profiles with measured data. Point‐doses in a water medium are found to be within 2% agreement of commissioning data in 99.5% and 98.6% of the points computed by MC and CC, respectively. All point‐dose calculations for the eMC algorithm in water are within 4% agreement of measurement, and 92% of measurements are within 3%. In heterogeneous media of air and cortical bone, both CC and MC yielded better than 3% agreement with ion chamber measurements. eMC yielded 3% agreement to measurement downstream of air with oblique beams of up to 27°, 5% agreement distal to bone, and within 4% agreement at extended source to surface distance (SSD) for all electron energies except 6 MeV. The 6‐MeV point of measurement is on a steep dose gradient which may impact the magnitude of discrepancy measured. The average gamma passing rate for IMRT/VMAT plans is 96.9% (±2.1%) and 98.0% (±1.9%) for VMAT SBRT when evaluated using 3%/2 mm criteria. Monaco beam models for the Versa HD linac were successfully commissioned for clinical use.
To present a system for the treatment of prostate cancer in a single-fraction regimen using
Yb-based rotating shield brachytherapy (RSBT) with a single-catheter robotic delivery system. The proposed ...system is innovative because it can deliver RSBT through multiple implanted needles independently, in serial, using flexible catheters, with no inter-needle shielding effects and without the need to rotate multiple shielded catheters inside the needles simultaneously, resulting in a simple, mechanically robust, delivery approach. RSBT was compared to conventional
Ir-based high-dose-rate brachytherapy (HDR-BT) in a treatment planning study with dose escalation and urethral sparing goals, representing single-fraction brachytherapy monotherapy and brachytherapy as a boost to external beam radiotherapy, respectively. A prototype mechanical delivery system was constructed and quantitatively evaluated as a proof of concept.
Treatment plans for twenty-six patients with single fraction prescriptions of 20.5 and 15 Gy, were created for dose escalation and urethral sparing, respectively. The RSBT and HDR-BT delivery systems were modeled with one partially shielded 999 GBq (27 Ci)
Yb source and one 370 GBq (10 Ci)
Ir source, respectively. A prototype angular drive system for helical source delivery was constructed. Mechanical accuracy measurements of source translational position and angular orientation in a simulated treatment delivery setup were obtained using the prototype system.
For dose escalation, with equivalent urethra D
, PTV D
for RSBT vs HDR-BT increased from 22.6 ± 0.0 Gy (average ± standard deviation) to 29.3 ± 0.9 Gy, or 29.9 % ± 3.0%, with treatment times of 51.4 ± 6.1 min for RSBT and 15.8 ± 2.3 min for 10 Ci
Ir-based HDR-BT. For urethra sparing, with equivalent PTV D
, urethra D
for RSBT vs HDR-BT decreased for RSBT vs HDR-BT from 15.6 ± 0.4 Gy to 12.0 ± 0.4 Gy, or 23.1% ± 3.5%, with treatment times of 30.0 ± 3.7 min for RSBT and 12.3 ± 1.8 min for HDR-BT. Differences between measured vs predicted rotating catheter positions (corresponding to source position) were within 0.18 mm ± 0.12 mm longitudinally and 0.07° ± 0.78°.
Yb-based RSBT can increase PTV D
or decrease urethral D
relative to HDR-BT with treatment times of less than 1 h using a single-source robotic delivery system with treatment delivered in a single fraction. The prototype helical delivery system was able to demonstrate adequate mechanical accuracy.
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