Relative thoracic changes from supine to upright patient position: A proton collaborative group study.

This study presents position changes of a few radiotherapy-relevant thoracic organs between upright and typical supine patient orientations. Using tools in a commercial treatment planning system (TPS), key anatomical distances were measured for four-dimensional CT data sets and analyzed for the two patient orientations. The uncertainty was calculated as the 95% confidence interval (CI) on the relative difference for each of the four analyzed changes for upright relative to supine, as follows: the distance of the bottom of the heart to the top of the sternum, it changed +2.6% or +4 mm (95% CI [+0.30%,+4.9%]); the distance of the center of the C3 vertebra to the backrest, it changed +29% (95% CI [+22%,+36%]); the contoured left and right lungs increased their volumes respectively: +17% (95% CI [+12%,+21%]) for the left, and +9.9% (95% CI [+4.1%,+16%]); and lastly, the distance from the top of the sternum to the top of the liver, but its uncertainty far exceeded the average change by a factor of two. This last result is therefore inconclusive, the others show that with 95% confidence that a change in internal positions is observed for lung volumes and heart position that could be important for upright treatments.

Anatomical changes in the male pelvis between the supine and upright positions-A feasibility study for prostate treatments in the upright position.

Treating and imaging patients in the upright orientation is gaining acceptance in radiation oncology and radiology and has distinct advantages over the recumbent position. An IRB approved study to investigate the positions and orientations of the male pelvic organs between the supine and upright positions was conducted. The study comprised of scanning 15 male volunteers (aged 55-75 years) on a 0.6 T Fonar MRI scanner in the supine and upright positions with a full bladder and in the upright position with an empty bladder. The Pelvic study revealed that in the upright position the 1. Position and shape of the prostate are not impacted significantly by bladder fill. 2. Distance between the sacrum and the anterior bladder wall is significantly smaller. 3. Anterior-Posterior length and the bladder width is significantly larger. 4. Seminal vesicles are pushed down by the bladder. 5. Top of the penile bulb is further away from the apex of the prostate. These observed differences could positively impact upright prostate treatments by 1. Reducing the risk of small bowel approximating the treatment volume. 2. Prostate treatments can be done with a reduced focus on bladder fill. 3. Radiation beams for treating intermediate risk prostrate can be made smaller or a larger portion of the seminal vesicles can be treated with the same beam size than typically used for supine treatments. 4. Reducing the average dose to the penile bulb.

The use of image synthesis techniques in target and roi delineation in the upright position.

The use of multi-modality imaging technologies such as CT, MRI, and PET imaging is state of the art for radiation therapy treatment planning. Except for a limited number of low magnetic field MR scanners the majority of such imaging technologies can only image the patient in a recumbent position. Delivering radiation therapy treatments with the patient in an upright orientation has many benefits and several companies are now developing upright patient positioners combined with upright diagnostic helical CT scanners to facilitate upright radiation therapy treatments. Due to the directional changes in the gravitational forces on the patient's body, most structures and organs will change position and shape between the recumbent and upright positions. Detailed knowledge about such structures and organs are therefore often only available in the recumbent position. The problem statement is therefore well defined, that is, how do we know where such structures and organs, that is, the target or region at risk volumes, are in the upright position if those cannot be identified and or delineated accurately enough using the upright diagnostic quality CT images only? This paper outlines two methods based on synthetic CT or MR images to overcome this problem.

Proposing a Clinical Model for RBE Based on Proton Track-End Counts.

PURPOSE: In proton therapy, the clinical application of linear energy transfer (LET) optimization remains contentious, in part because of challenges associated with the definition and calculation of LET and its exact relationship with relative biological effectiveness (RBE) because of large variation in experimental in vitro data. This has raised interest in other metrics with favorable properties for biological optimization, such as the number of proton track ends in a voxel. In this work, we propose a novel model for clinical calculations of RBE, based on proton track end counts. METHODS AND MATERIALS: We developed an effective dose concept to translate between the total proton track-end count per unit mass in a voxel and a proton RBE value. Dose, track end, and dose-averaged LET (LETd) distributions were simulated using Monte Carlo models for a series of water phantoms, in vitro radiobiological studies, and patient treatment plans. We evaluated the correlation between track ends and regions of elevated biological effectiveness in comparison to LETd-based models of RBE. RESULTS: Track ends were found to correlate with biological effects in in vitro experiments with an accuracy comparable to LETd. In patient simulations, our track end model identified the same biological hotspots as predicted by LETd-based radiobiological models of proton RBE. CONCLUSIONS: These results suggest that, for clinical optimization and evaluation, an RBE model based on proton track end counts may match LETd-based models in terms of information provided while also offering superior statistical properties.

A systematic review of clinical studies on variable proton Relative Biological Effectiveness (RBE).

Recently, a number of clinical studies have explored links between possible Relative Biological Effectiveness (RBE) elevations and patient toxicities and/or image changes following proton therapy. Our objective was to perform a systematic review of such studies. We applied a "Problem [RBE], Intervention [Protons], Population [Patients], Outcome [Side effect]" search strategy to the PubMed database. From our search, we retrieved studies which: (a) performed novel voxel-wise analyses of patient effects versus physical dose and LET (n = 13), and (b) compared image changes between proton and photon cohorts with regard to proton RBE (n = 9). For each retrieved study, we extracted data regarding: primary tumour type; size of patient cohort; type of image change studied; image-registration method (deformable or rigid); LET calculation method, and statistical methodology. We compared and contrasted their methods in order to discuss the weight of clinical evidence for variable proton RBE. We concluded that clinical evidence for variable proton RBE remains statistically weak at present. Our principal recommendation is that proton centres and clinical trial teams collaborate to standardize follow-up protocols and statistical analysis methods, so that larger patient cohorts can ultimately be considered for RBE analyses.

A Monte Carlo study of different LET definitions and calculation parameters for proton beam therapy.

The strongin vitroevidence that proton Relative Biological Effectiveness (RBE) varies with Linear Energy Transfer (LET) has led to an interest in applying LET within treatment planning. However, there is a lack of consensus on LET definition, Monte Carlo (MC) parameters or clinical methodology. This work aims to investigate how common variations of LET definition may affect potential clinical applications. MC simulations (GATE/GEANT4) were used to calculate absorbed dose and different types of LET for a simple Spread Out Bragg Peak (SOBP) and for four clinical PBT plans covering a range of tumour sites. Variations in the following LET calculation methods were considered: (i) averaging (dose-averaged LET (LETd) & track-averaged LET); (ii) scoring (LETdto water, to medium and to mass density); (iii) particle inclusion (LETdto all protons, to primary protons and to particles); (iv) MC settings (hit type and Maximum Step Size (MSS)). LET distributions were compared using: qualitative comparison, LET Volume Histograms (LVHs), single value criteria (maximum and mean values) and optimised LET-weighted dose models. Substantial differences were found between LET values in averaging, scoring and particle type. These differences depended on the methodology, but for one patient a difference of ∼100% was observed between the maximum LETdfor all particles and maximum LETdfor all protons within the brainstem in the high isodose region (4 keVµm-1and 8 keVµm-1respectively). An RBE model using LETdincluding heavier ions was found to predict substantially different LET-weighted dose compared to those using other LET definitions. In conclusion, the selection of LET definition may affect the results of clinical metrics considered in treatment planning and the results of an RBE model. The authors' advocate for the scoring of dose-averaged LET to water for primary and secondary protons using a random hit type and automated MSS.

Does the uncertainty in relative biological effectiveness affect patient treatment in proton therapy?

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective.

Reply to comment on 'origins of the changing detector response in small megavoltage photon radiation fields'.

Andreo and Benmakhlouf (2017 Phys. Med. Biol. 62 1518-32) have disputed a finding of Scott et al (2012 Phys. Med. Biol. 57 4461-76) that the variation with field-size of the response of small ion chambers and solid-state dosimeters in small megavoltage photon radiation fields can largely be attributed to density. Further evidence for this finding was provided by Fenwick et al (2018 Phys. Med. Biol. 63 125003), but Andreo and Benmakhlouf (2018 Phys. Med. Biol. 63 125003) have now challenged the methodology used in that study. Specifically, Andreo and Benmakhlouf suggest that mass stopping-powers of fictitious materials used in Monte Carlo radiation transport calculations should be adjusted with material density according to the polarization effect, as if the materials were real and created by compressing other real materials. In this reply, we observe that fictitious materials are not real, and therefore their densities, mass stopping-powers and microscopic radiation interaction cross-sections can be freely and independently chosen to provide the clearest answers to the questions being studied. And we note that the key role played by density in small field detector response was further confirmed by our group back in 2013, using fictitious materials in which mass stopping-powers were adjusted with density, as preferred by Andreo and Benmakhlouf, as well as being held fixed, with very similar results being obtained in both circumstances (Underwood et al 2013a Med. Phys. 40 082102).

Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1.

PURPOSE: Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but in vitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1. METHODS AND MATERIALS: We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4 Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist. RESULTS: Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and ΔHU/Gy (RBE) (endpoint 2): P = .049 and P = .00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P = .018; median score, 3 of 9 for protons and 1.5 of 9 for photons). CONCLUSIONS: Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important in vivo as well as in vitro.

Origins of the changing detector response in small megavoltage photon radiation fields.

Differences in detector response between measured small fields, f clin, and wider reference fields, f msr , can be overcome by using correction factors [Formula: see text] or by designing detectors with field-size invariant responses. The changing response in small fields is caused by perturbations of the electron fluence within the detector sensitive volume. For solid-state detectors, it has recently been suggested that these perturbations might be caused by the non-water-equivalent effective atomic numbers Z of detector materials, rather than by their non-water-like densities. Using the EGSnrc Monte Carlo code we have analyzed the response of a PTW 60017 diode detector in a 6 MV beam, calculating the [Formula: see text] correction factor from computed doses absorbed by water and by the detector sensitive volume in 0.5 × 0.5 and 4 × 4 cm2 fields. In addition to the 'real' detector, fully modelled according to the manufacturer's blue-prints, we calculated doses and [Formula: see text] factors for a 'Z → water' detector variant in which mass stopping-powers and microscopic interaction coefficients were set to those of water while preserving real material densities, and for a 'density → 1' variant in which densities were set to 1 g cm-3, leaving mass stopping-powers and interaction coefficients at real levels. [Formula: see text] equalled 0.910 ± 0.005 (2 standard deviations) for the real detector, was insignificantly different at 0.912 ± 0.005 for the 'Z → H2O' variant, but equalled 1.012 ± 0.006 for the 'density → 1' variant. For the 60017 diode in a 6 MV beam, then, [Formula: see text] was determined primarily by the detector's density rather than its atomic composition. Further calculations showed this remained the case in a 15 MV beam. Interestingly, the sensitive volume electron fluence was perturbed more by detector atomic composition than by density; however, the density-dependent perturbation varied with field-size, whereas the Z-dependent perturbation was relatively constant, little affecting [Formula: see text].

Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams.

AIM: Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon α/ß. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered. RESULTS: For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative α/ß = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, ≤10% of the rectum received ≥20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely. CONCLUSION: Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear.

Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation.

PURPOSE: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ∼1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation. METHODS AND MATERIALS: Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/µm) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison. RESULTS: Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage. CONCLUSIONS: A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.