. To investigate similarities and differences in the formalism, processing, and the results of relative biological effectiveness (RBE) calculations with a biological weighting function (BWF), the ...microdosimetric kinetic model (MKM) and subsequent modifications (non-Poisson MKM, modified MKM). This includes: (a) the extension of the V79-RBE
BWF to model the RBE for other clonogenic survival levels; (b) a novel implementation of MKMs as weighting functions; (c) a benchmark against Chinese Hamster lung fibroblast (V79)
data; (d) a study on the effect of pre- or post- processing the average biophysical quantities used for the RBE calculations; (e) a possible modification of the modified MKM parameters to improve the model accuracy at high linear energy transfer (LET).
. Lineal energy spectra were simulated for two spherical targets (diameter = 0.464 or 1.0
m) using PHITS for
H,
He,
C,
Ne,
Ar,
Fe and
Xe ions. The results of the
calculations were compared with published
data.
. All models appear to underestimate the RBE
of hydrogen ions. All MKMs generally overestimate the RBE
, RBE
and RBE
for ions with an LET greater than ∼200 keV
m
. This overestimation is greater for small surviving fractions and is likely due to the assumption of a radiation-independent quadratic term of clonogenic survival (
). The overall RBE trends seem to be best described by the novel 'post-processing average' implementation of the non-Poisson MKM. In case of calculations with the non-Poisson MKM, pre- or post- processing the average biophysical quantities affects the computed RBE values significantly.
. This study presents a systematic analysis of the formalism and results of widely used microdosimetric models of clonogenic survival for ions relevant for cancer particle therapy and space radiation protection. Points for improvements were highlighted and will contribute to the development of upgraded biophysical models.
. (1) To examine to what extent the cell- and exposure- specific information neglected in the phenomenological proton relative biological effectiveness (RBE) models could influence the computed RBE ...in proton therapy. (2) To explore similarities and differences in the formalism and the results between the linear energy transfer (LET)-based phenomenological proton RBE models and the microdosimetry-based Mayo Clinic Florida microdosimetric kinetic model (MCF MKM). (3) To investigate how the relationship between the RBE and the dose-mean proton LET is affected by the proton energy spectrum and the secondary fragments.
. We systematically compared six selected phenomenological proton RBE models with the MCF MKM in track-segment simulations, monoenergetic proton beams in a water phantom, and two spread-out Bragg peaks. A representative comparison with
data for human glioblastoma cells (U87 cell line) is also included.
. Marked differences were observed between the results of the phenomenological proton RBE models, as reported in previous studies. The dispersion of these models' results was found to be comparable to the spread in the MCF MKM results obtained by varying the cell-specific parameters neglected in the phenomenological models. Furthermore, while single cell-specific correlation between RBE and the dose-mean proton LET seems reasonable above 2 keV
m
, caution is necessary at lower LET values due to the relevant contribution of secondary fragments. The comparison with
data demonstrates comparable agreement between the MCF MKM predictions and the results of the phenomenological models.
. The study highlights the importance of considering cell-specific characteristics and detailed radiation quality information for accurate RBE calculations in proton therapy. Furthermore, these results provide confidence in the use of the MCF MKM for clonogenic survival RBE calculations in proton therapy, offering a more mechanistic approach compared to phenomenological models.
The relative biological effectiveness (RBE) calculations used during the planning of ion therapy treatments are generally based on the microdosimetric kinetic model (MKM) and the local effect model ...(LEM). The Mayo Clinic Florida MKM (MCF MKM) was recently developed to overcome the limitations of previous MKMs in reproducing the biological data and to eliminate the need for ion-exposed in vitro data as input for the model calculations. Since we are considering to implement the MCF MKM in clinic, this article presents (a) an extensive benchmark of the MCF MKM predictions against corresponding in vitro clonogenic survival data for 4 rodent and 10 cell lines exposed to ions from 1H to 238U, and (b) a systematic comparison with published results of the latest version of the LEM (LEM IV). Additionally, we introduce a novel approach to derive an approximate value of the MCF MKM model parameters by knowing only the animal species and the mean number of chromosomes. The overall good agreement between MCF MKM predictions and in vitro data suggests the MCF MKM can be reliably used for the RBE calculations. In most cases, a reasonable agreement was found between the MCF MKM and the LEM IV.
We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell ...carcinoma models. We compared the SABR-induced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1-blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11a(high) CD8(+) T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer.
Background
Discrete spot scanning (DSS) is the commonly used method for proton pencil beam scanning (PBS). There is lack of data on the dose‐driven continuous scanning (DDCS).
Purpose
To investigate ...delivery benefits and dosimetric implications of DDCS versus DSS for PBS systems.
Methods
The irradiation duty factor, beam delivery time (BDT), and dose deviation were simulated for eight treatment plans in prostate, head and neck, liver, and lung, with both conventional fractionation and hypofractionation schemes. DDCS results were compared with those of DSS.
Results
The DDCS irradiation duty factor (range, 11%–41%) was appreciably improved compared to DSS delivery (range, 4%–14%), within which, hypofractionation schemes had greater improvement than conventional fractionation. With decreasing stop ratio constraints, the DDCS BDT reduction was greater, but dose deviation also increased. With stop ratio constraints of 2, 1, 0.5, and 0, DDCS BDT reduction reached to 6%, 10%, 12%, and 15%, respectively, and dose deviation reached to 0.6%, 1.7%, 3.0%, and 5.2% root mean square error in PTV DVH, respectively. The 3%/2‐mm gamma passing rate was greater than 99% with stop ratio constraints of 2 and 1, and greater than 95% with a stop ratio of 0.5. When the stop ratio constraint was removed, five of the eight treatment plans had a 3%/2‐mm gamma passing rate greater than 95%, and the other three plans had a 3%/2‐mm gamma passing rate between 90% and 95%.
Conclusions
The irradiation duty factor was considerably improved with DDCS. Smaller stop ratio constraints led to shorter BDTs, but with the cost of larger dose deviations. Our finding suggested that a stop ratio of 1 constraint seems to yield acceptable DDCS dose deviation.
Purpose
To investigate the beam delivery time (BDT) reduction due to the improvement of machine parameters for Hitachi synchrotron-based proton PBS system.
Methods
BDTs for representative treatment ...plans were calculated to quantitatively estimate the BDT improvement from our 2015 system at Mayo Clinic in Arizona to our system to be implemented in 2025 at Mayo Clinic in Florida, and to a hypothetical future system. To specifically assess how each incremental improvement in the operating parameters reduced the total BDT, for each plan, we simulated the BDT 10,368 times with various settings of the nine different operating parameters. The effect of each operating parameter on BDT reduction and its correlation with treatment plan characteristics were analyzed. The optimal number of multiple energy extraction (MEE) layers per spill for different systems was also investigated.
Results
The median (range) decrease in BDT was 60% (56%-70%) from the 2015 to the 2025 system. The following incremental improvement in parameters of the 2015 system for the 2025 system played an important role in this decreased BDT: beam intensity (8 to 20 MU/s), recapture efficiency (50% to 80%), number of MEE layers per spill (4 to 8), scanning magnet preparation and verification time (1.9 to 0.95 msec), and MEE layer switch time (200 to 100 msec). Reducing the total spill change time and scanning magnet preparation and verification time from those of the 2025 system further reduced BDT in the hypothetical future system. 8 MEE layers per spill is optimal for a system with 50% recapture efficiency; 16 MEE layers per spill is optimal for a system with 80% recapture efficiency; and more than 16 MEE layers per spill is beneficial only for a system close to 100% recapture efficiency.
Conclusions
We systematically studied the effect of each machine operating parameter on the reduction in total BDT and its correlation with treatment plan characteristics. Our findings will aid new and existing synchrotron-based proton beam therapy centers to make balanced decisions on BDT benefits vs. costs when considering machine upgrade or new system selection.
Abstract
The Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) is a recently developed clonogenic survival model. Since the MCF MKM relies on novel strategies to a priori determine the ...cell-specific model parameters, the only experiment-specific input values are the α and ß terms of the linear–quadratic model (LQM) of clonogenic survival for the reference photon exposure. Because the two LQM terms are anti-correlated, the fitting process of the reference photon survival curve was found to significantly influence the MCF MKM calculations. This article reports this effect for two clinically relevant cell lines (human brain glioblastoma A-172, human healthy foreskin fibroblasts AG01522) and ions (1H and 12C ions).
Abstract
Measurements of the extracted beam current (BC) for a Hitachi Carbon Therapy Synchrotron and a Hitachi Compact Proton Therapy Synchrotron are reported for the nominal extracted beam current ...(BC0) of
10
m
M
U
m
sec
, which was chosen since it is the magnitude of the clinical BC0, and a sample rate of 5
μ
sec (Carbon) and 8
μ
sec (Proton). A Noise Power Spectrum (NPS) analysis identifies the source of variation to be beam or power supply related. The rise time in the BC has been modeled and its effect on beam delivery time simulations have been estimated. The impact of the variation in BC from BC0 is shown to cause potentially significant dosimetric uncertainties in treatment delivery for modern particle therapy accelerators using fast Scanning Magnet (SCM) if plans are not simply beam current moderated or robustly optimized. The variation in beam current is shown to be inconsequential for medical physics quality assurance and commissioning measurements using properly biased ion chambers.
Background
Using the pencil beam raster scanning method employed at most carbon beam treatment facilities, spots can be moved without interrupting the beam, allowing for the delivery of a dose ...between spots (move dose). This technique is also known as Dose‐Driven‐Continuous‐Scanning (DDCS). To minimize its impact on HIMAK patient dosimetry, there's an upper limit to the move dose. Spots within a layer are grouped into sets, or “break points,” allowing continuous irradiation. The beam is turned off when transitioning between sets or at the end of a treatment layer or spill. The control system beam‐off is accomplished by turning off the RF Knockout (RFKO) extraction and after a brief delay the High Speed Steering Magnet (HSST) redirects the beam transport away from isocenter to a beam dump.
Purpose
The influence of the move dose and beam on/off control on the dose distribution and irradiation time was evaluated by measurements never before reported and modelled for Hitachi Carbon DDCS.
Method
We conducted fixed‐point and scanning irradiation experiments at three different energies, both with and without breakpoints. For fixed‐point irradiation, we utilized a 2D array detector and an oscilloscope to measure beam intensity over time. The oscilloscope data enabled us to confirm beam‐off and beam‐on timing due to breakpoints, as well as the relative timing of the RFKO signal, HSST signal, and dose monitor (DM) signals. From these measurements, we analyzed and modelled the temporal characteristics of the beam intensity. We also developed a model for the spot shape and amplitude at isocenter occurring after the beam‐off signal which we called flap dose and its dependence on beam intensity. In the case of scanning irradiation, we measured move doses using the 2D array detector and compared these measurements with our model.
Result
We observed that the most dominant time variation of the beam intensity was at 1 kHz and its harmonic frequencies. Our findings revealed that the derived beam intensity cannot reach the preset beam intensity when each spot belongs to different breakpoints. The beam‐off time due to breakpoints was approximately 100 ms, while the beam rise time and fall time (tdecay) were remarkably fast, about 10 ms and 0.2 ms, respectively. Moreover, we measured the time lag (tdelay) of approximately 0.2 ms between the RFKO and HSST signals. Since tdelay ≈ tdecay at HIMAK then the HSST is activated after the residual beam intensity, resulting in essentially zero flap dose at isocenter from the HSST. Our measurements of the move dose demonstrated excellent agreement with the modelled move dose.
Conclusion
We conducted the first move dose measurement for a Hitachi Carbon synchrotron, and our findings, considering beam on/off control details, indicate that Hitachi's carbon synchrotron provides a stable beam at HIMAK. Our work suggests that measuring both move dose and flap dose should be part of the commissioning process and possibly using our model in the Treatment Planning System (TPS) for new facilities with treatment delivery control systems with higher beam intensities and faster beam‐off control.
Radiochromic film (RCF) is a valuable dosimetric tool, primarily due to its sub-millimeter spatial resolution. For accurate proton dosimetry, the dependence of film response on linear energy transfer ...(LET) must be characterized and calibrated. In this work, we characterized film under-response, or 'quenching', as a function of dose-weighted linear energy transfer (LETd) in several proton fields and established a simple, linear relationship with LETd. We performed measurements as a function of depth in a PMMA phantom irradiated by a spot-scanning proton beam. The fields had energies of 71.3 MeV, 71.3 MeV with filter, and 159.9 MeV. At each depth (measurements taken in depth step sizes of 0.5-1 mm in the Bragg peak), we measured dose with a PTW Markus ion chamber and EBT3 RCF. EBT3 under-response was characterized by the ratio of dose measured with film to that with ion chamber. LETd values for our experimental setup were calculated using in-house clinical Monte Carlo code. Measured film under-response increased with LETd, from approximately 10% under-response for LETd = 5 keV µm−1 to approximately 20% for LETd = 8 keV µm−1. The under-response for all measurements was plotted versus LETd. A linear fit to the data was performed, yielding a function for under-response, , with respect to LETd: . Finally, the linear under-response relationship was applied to a film measurement within a spread-out Bragg peak (SOBP). Without correcting for LETd-dependence in the SOBP measurement, the discrepancy between film and Monte Carlo profiles was greater than 15% at the distal edge. With correction, the corrected film profile was within 2% and 1 mm of the Monte Carlo profile. RCF response depends on LETd, potentially under-responding by >15% in clinically-relevant scenarios. Therefore, it is insufficient to perform only a dose calibration; LET calibration is also necessary for accurate proton film dosimetry. The LETd-dependence of EBT3 can be described by a single, linear function over a range of clinically-relevant proton therapy LETd values.
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