Purpose Late-occurring contrast-enhancing brain lesions (CEBLs) have been observed on MRI follow-up in low-grade glioma (LGG) patients post-proton therapy. Predictive risk-models for this endpoint identified a dose-averaged linear energy transfer (LETd)-dependent proton relative biological effectiveness (RBE) effect on CEBL occurrence and increased radiosensitivity of the cerebral periventricular region (VP4mm). This work aimed to design a stable risk-minimizing treatment planning (TP) concept addressing these intertwined risk factors through a classically formulated optimization problem. Material and methods The concept was developed in RayStation-research 11B IonPG featuring a variable-RBE-based optimizer involving 20 LGG patients with varying target volume localizations and risk-factor contributions. Classical cost functions penalizing dose, dose-volume-histogram points, and equivalent uniform dose were used to formulate the optimization problem, and a new set of structures was introduced to actively spare the VP4mm, control high LETd regions, and de-escalate the dose outside the gross tumor volume. Target volume coverage and organ-at-risk sparing were robustly evaluated, and Normal Tissue Complication Probabilities (NTCP) for CEBL occurrence were quantified. Results The concept yielded stable optimization outcomes for all considered subjects. Risk hot spots were successfully mitigated, and an NTCP reduction of up to 79 % was observed compared to conventional TP while maintaining target coverage, demonstrating the feasibility of the chosen model-based approach. Conclusion With the proposed TP protocol, we close the gap between predictive risk-modeling and practical risk-mitigation in the clinic and provide a concept for CEBL avoidance with the potential to advance treatment precision for LGG patients.

Positron emission tomography (PET) and prompt gamma (PG) detection are promising proton therapy monitoring modalities. Fast calculation of the expected distributions is desirable for comparison to measurements and to develop/train algorithms for automatic treatment error detection. A filtering formalism was used for positron-emitter predictions and adapted to allow for its use for the beamline of any proton therapy centre. A novel approach based on a filtering formalism was developed for the prediction of energy-resolved PG distributions for arbitrary tissues. The method estimates PG yields and their energy spectra in the entire treatment field. Both approaches were implemented in a research version of the RayStation treatment planning system. The method was validated against PET monitoring data and Monte Carlo simulations for four patients treated with scanned proton beams. Longitudinal shifts between profiles from analytical and Monte Carlo calculations were within -1.7 and 0.9 mm, with maximum standard deviation of 0.9 mm and 1.1 mm, for positron-emitters and PG shifts, respectively. Normalized mean absolute errors were within 1.2 and 5.3%. When comparing measured and predicted PET data, the same more complex case yielded an average shift of 3 mm, while all other cases were below absolute average shifts of 1.1 mm. Normalized mean absolute errors were below 7.2% for all cases. A novel solution to predict positron-emitter and PG distributions in a treatment planning system is proposed, enabling calculation times of only a few seconds to minutes for entire patient cases, which is suitable for integration in daily clinical routine.

Purpose: Validate implementation of a published RBE model for DSB induction (RBEDSB) in several general purpose Monte Carlo (MC) code systems and the RayStation™ treatment planning system (TPS). For protons and other light ions, DSB induction is a critical initiating molecular event that correlates well with the RBE for cell survival. Methods: An efficient algorithm to incorporate information on proton and light ion RBEDSB from the independently tested Monte Carlo Damage Simulation (MCDS) has now been integrated into MCNP (Stewart et al. PMB 60, 8249–8274, 2015), FLUKA, TOPAS and a research build of the RayStation™ TPS. To cross-validate the RBEDSB model implementation LET distributions, depth-dose and lateral (dose and RBEDSB) profiles for monodirectional monoenergetic (100 to 200 MeV) protons incident on a water phantom are compared. The effects of recoil and secondary ion production (2H+, 3H+, 3He2+, 4He2+), spot size (3 and 10 mm), and transport physics on beam profiles and RBEDSB are examined. Results: Depth-dose and RBEDSB profiles among all of the MC models are in excellent agreement using a 1 mm distance criterion (width of a voxel). For a 100 MeV proton beam (10 mm spot), RBEDSB = 1.2 ± 0.03 (− 2–3%) at the tip of the Bragg peak and increases to 1.59 ± 0.3 two mm distal to the Bragg peak. RBEDSB tends to decrease as the kinetic energy of the incident proton increases. Conclusion: The model for proton RBEDSB has been accurately implemented into FLUKA, MCNP, TOPAS and the RayStation™TPS. The transport of secondary light ions (Z > 1) has a significant impact on RBEDSB, especially distal to the Bragg peak, although light ions have a small effect on (dosexRBEDSB) profiles. The ability to incorporate spatial variations in proton RBE within a TPS creates new opportunities to individualize treatment plans and increase the therapeutic ratio. Dr. Erik Traneus is employed full-time as a Research Scientist at RaySearch Laboratories. The research build of the RayStation used in the study was made available to the University of Washington free of charge. RaySearch Laboratories did not provide any monetary support for the reported studies.

Proton therapy utilizes the unique properties of the Bragg peak to create highly conformal treatments for head and neck (HN) and brain tumors. However, spatial variations in proton relative biological effectiveness (RBE) near beam edges and beyond the tip of the Bragg peak may create biological hot spots with the potential to increase treatment complications, especially for organs at risk (OAR) close to or within the target volume. We used a newly implemented Monte Carlo (MC) model in the RayStationä treatment planning system (TPS) to retrospectively examine the impact of spatial variations in proton RBE on tumor targets and selected OAR. A research build of Raystationä combines a new MC dose algorithm with a published model for DNA double strand break (DSB) induction as a function of proton linear energy transfer (LET). Trends in the model computed RBE for DSB induction with proton LET are predictive of trends in reproductive cell survival in vitro. Dose and (RBE x dose) distributions were re-computed using the RayStationä for 8 patients treated with pencil beam scanning to the brain (frontal or temporal lobe) or HN (nasopharynx, tonsils, base of tongue). Dose-averaged RBE values were computed by dividing the (RBE x absorbed dose) for the tumor and OAR volume by the average absorbed dose to the same volume without corrections for spatial variations in proton RBE. The anatomy-specific RBE estimates were determined for the composite plan (2-5 beams) as well as on a beam by beam basis. To identify putative biological hot and cold spots, plans that correct for spatial variations in proton RBE were compared to plans with a constant (spatially invariant) RBE of 1.1. Among all patients, the composite-plan tumor RBE ranged from 1.02 to 1.10, whereas the RBE for the OAR of concern varied from 1.03 to 1.33 for the composite plans. The composite-plan RBE was 1.13 + 0.1 and 1.21 + 0.12 for the brainstem and optic apparati, respectively. In one patient plan, a biological hot spot (RBE = 1.43) was created by a beam at the surface of the brainstem. Although the RBE model integrated into the TPS only depends on the proton energy and LET, the patient anatomy and the number and orientation of the beams directed at the treatment volume create a unique, patient-specific spatial pattern (distribution) of LET and RBE values. Anatomy-specific estimates of the RBE for DSB induction can differ by as much +13% for treatment limiting OAR. Differences in RBE estimates among patients suggests that biological optimization of (variable RBE x dose) might be exploited to reduce treatment complications and increase the therapeutic ratio, perhaps by as much as 25-30% of the total treatment dose.

Purpose:Compare proton pencil beam scanning dose measurements to GATE/GEANT4 (GMC) and RayStation™ Monte Carlo (RMC) simulations.Methods:Proton pencil beam models of the IBA gantry at the Seattle Proton Therapy Center were developed in the GMC code system and a research build of the RMC. For RMC, a preliminary beam model that does not account for upstream halo was used. Depth dose and lateral profiles are compared for the RMC, GMC and a RayStation™ pencil beam dose (RPB) model for three spread out Bragg peaks (SOBPs) in homogenous water phantom. SOBP comparisons were also made among the three models for a phantom with a (i) 2 cm bone and a (ii) 0.5 cm titanium insert.Results:Measurements and GMC estimates of R80 range agree to within 1 mm, and the mean point‐to‐point dose difference is within 1.2% for all integrated depth dose (IDD) profiles. The dose differences at the peak are 1 to 2%. All of the simulated spot sigmas are within 0.15 mm of the measured values. For the three SOBPs considered, the maximum R80 deviation from measurement for GMC was −0.35 mm, RMC 0.5 mm, and RPB −0.1 mm. The minimum gamma pass using the 3%/3mm criterion for all the profiles was 94%. The dose comparison for heterogeneous inserts in low dose gradient regions showed dose differences greater than 10% at the distal edge of interface between RPB and GMC. The RMC showed improvement and agreed with GMC to within 7%.Conclusion:The RPB dosimetry show clinically significant differences (> 10%) from GMC and RMC estimates. The RMC algorithm is superior to the RPB dosimetry in heterogeneous media. We suspect modelling of the beam's halo may be responsible for a portion of the remaining discrepancy and that RayStation will reduce this discrepancy as they finalize the release.Erik Traneus is employed as a Research Scientist at RaySearch Laboratories. The research build of the RayStation TPS used in the study was made available to the SCCA free of charge. RaySearch did not provide any monetary support other than a license to use the research build of the TPS.

Purpose:We describe and demonstrate a fast analytical tool for prompt‐gamma emission prediction based on filter functions applied on the depth dose profile. We present the implementation in a treatment planning system (TPS) of the same algorithm for positron emitter distributions.Methods:The prediction of the desired observable is based on the convolution of filter functions with the depth dose profile. For both prompt‐gammas and positron emitters, the results of Monte Carlo simulations (MC) are compared with those of the analytical tool. For prompt‐gamma emission from inelastic proton‐induced reactions, homogeneous and inhomogeneous phantoms alongside with patient data are used as irradiation targets of mono‐energetic proton pencil beams. The accuracy of the tool is assessed in terms of the shape of the analytically calculated depth profiles and their absolute yields, compared to MC. For the positron emitters, the method is implemented in a research RayStation TPS and compared to MC predictions. Digital phantoms and patient data are used and positron emitter spatial density distributions are analyzed.Results:Calculated prompt‐gamma profiles agree with MC within 3 % in terms of absolute yield and reproduce the correct shape. Based on an arbitrary reference material and by means of 6 filter functions (one per chemical element), profiles in any other material composed of those elements can be predicted. The TPS implemented algorithm is accurate enough to enable, via the analytically calculated positron emitters profiles, detection of range differences between the TPS and MC with errors of the order of 1–2 mm.Conclusion:The proposed analytical method predicts prompt‐gamma and positron emitter profiles which generally agree with the distributions obtained by a full MC. The implementation of the tool in a TPS shows that reliable profiles can be obtained directly from the dose calculated by the TPS, without the need of full MC simulation.

In a number of recent articles in this journal F. Cardone and collaborators have claimed the observation of several striking nuclear phenomena which they attribute to “piezonuclear reactions”. One such claim [F. Cardone, R. Mignani, A. Petrucci, Phys. Lett. A 373 (2009) 1956] is that subjecting a solution of 228Th to cavitation leads to a “transformation” of thorium nuclei that is 104 times faster than the normal nuclear decay for this isotope. In a “Comment” [G. Ericsson, S. Pomp, H. Sjöstrand, E. Traneus, Phys. Lett. A 373 (2009) 3795] to the thorium work, we have criticized the evidence provided for this claim. In a “Reply” [F. Cardone, R. Mignani, A. Petrucci, Phys. Lett. A 373 (2009) 3797] Cardone et al. answer only some minor points but avoid addressing the real issue. The information provided in their Reply displays a worrying lack of control of their experimental situation and the data they put forward as evidence for their claims. We point out several shortcomings and errors in the described experimental preparations, set-up and reporting, as well as in the data analysis. We conclude that the evidence presented by Cardone et al. is insufficient to justify their claims of accelerated thorium decay (by “piezonuclear reactions” or otherwise).

Use of a water-equivalent bolus in electron-beam radiotherapy is sometimes impractical and non-hygienic. Therefore, the feasibility of applying adjacent narrow beams for producing high surface dose electron beams without a bolus was investigated. Depth dose curves and profiles in water were calculated and measured for 6 and 9 MeV electron-beam segments (width 0.3–1.5 cm, length 10 cm) for source-to-surface distances (SSD) 102 and 105 cm. Segment shaping was performed with an add-on electron multi-leaf collimator prototype attached to the Varian 2100 C/D linac. Dose calculations were performed with the Voxel Monte Carlo++ algorithm. Resulting dose distributions in typical clinical cases were compared with the bolus technique. With a composite segmental field with 1.0 cm wide segments the surface dose was over 90% of the depth dose maximum for both energies. The build-up area practically disappeared with a 0.5 cm wide single beam. This led to decrease in the therapeutic range for composite fields with segment widths smaller than 1.0 cm. The new technique yielded similar surface doses as the bolus technique. The photon contamination was 4% with a 9 × 10 cm2 field (1.0 cm wide segments) compared to 1% for the respective open field with 9 MeV with a bolus. The calculated dose agreed within 2 mm and 3% of the measured dose in 93.7% and 85.2% of the voxels. Adjacent narrow eMLC beams with a 1.0 cm width are suitable to produce electron fields with high surface dose. Despite a slight nonuniformity in the surface profiles in the lateral part of the field at SSD 102 cm, surface dose and target coverage are comparable with the bolus technique.

Previously, we have found that the build-up dose from abutting narrow electron beams formed with unfocussed electron multi-leaf collimator (eMLC) steal leaves was higher than with the respective open field. To investigate more closely the effect of leaf material and shape on dose in the build-up region, straight, round (radius 1.5 cm) and leaf ends with a different front face angle of α (leaf front face pointing towards the beam axis at an angle of 90 − α) made of steel, brass and tungsten were modelled using the BEAMnrc code. Based on a treatment head simulation of a Varian 2100 C/D linac, depth–dose curves and profiles in water were calculated for narrow 6, 12 and 20 MeV eMLC beams (width 1.0 cm, length 10 cm) at source-to-surface distances (SSD) of 102 and 105 cm. The effects of leaf material and front face angle were evaluated based on electron fluence, angle and energy spectra. With a leaf front face angle of 15°, the dose in the build-up region of the 6 MeV field varied between 91 and 100%, while for straight and round leaf shapes the dose varied between 89 and 100%. The variation was between 94 and 100% for 12 and 20 MeV. For abutting narrow 6 MeV fields with total field size 5 × 10 cm2, the build-up doses at 5 mm depth for the face angle 15° and straight and round leaf shapes were 96% and 86% (SSD 102 cm) and 89% and 85% (SSD 105 cm). With higher energies, the effect of eMLC leaf shape on dose at 5 mm was slight (3–4% units with 12 MeV) and marginal with 20 MeV. The fluence, energy and angle spectra for total and leaf scattered electrons were practically the same for different leaf materials with 6 MeV. With high energies, the spectra for tungsten were more peaked due to lower leaf transmission. Compared with straight leaf ends, the face angle of 15° and round leaf ends led to a 1 mm (for 6 MeV) and between 1 and 5 mm (12 and 20 MeV at a SSD of 105 cm) decrease of therapeutic range and increase of the field size, respectively. However, profile flatness was better for abutting 6 MeV beams with round (2.5%) and face angle 15° leaves (3.0%) compared to straight leaf shape (5.2%). The eMLC leaves with a face angle of 15° resulted in a marked increase in the build-up dose for the single narrow eMLC beam and thus in the dose in the build-up region from matched abutting fields.

Subjecting a solution of 228Th to ultrasound (20 kHz, 100 W), Cardone et al. [F. Cardone, R. Mignani, A. Petrucci, Phys. Lett. A 373 (2009) 1956] claim to observe an increase in the transformation or decay rate of 228Th by a factor of 104. The evidence provided seems however far from conclusive and in part contradictory to the claims made. In fact, looking at the presented data we find it cannot be taken as justification to discard the null hypothesis, namely, that the data from exposed and non-exposed samples are drawn from the same distribution. We suggest a number of additional tests that should be made in order to improve the quality of the study and test the hypothesis of so-called piezonuclear reactions.

In a recent article F. Cardone et al. [Phys. Lett. A 373 (2009) 1956] have claimed that subjecting a solution of 228Th to cavitation leads to a "transformation" of the thorium nuclei that is 104 times faster than the normal nuclear decay for this isotope. We have criticized the evidence provided for this claim in a "Comment" [Phys. Lett. A (2009), in press, DOI 10.1016/j.physleta.2009.08.045]. In their "Reply" [Phys. Lett. A (2009), in press, DOI 10.1016/j.physleta.2009.08.047] Cardone et al. answer only some minor points but avoid addressing the real issue. They even state a new extraordinary claim, namely that the thorium "transformations" occur without emission of gamma rays. In addition, the information provided in their Reply displays a worrying lack of control of their experimental situation and the data they put forward as evidence for their claims. We point out several shortcomings and errors in the described experimental preparations, set-up and reporting, as well as in the data analysis. We conclude that the evidence presented by Cardone et al. is insufficient to justify their claims and that the shortcomings of their work are so severe that the original paper and the Reply should be withdrawn.

Dosimetric verification of a new Monte Carlo beam model for multi-leaf collimated electrons was performed using experimental data from an add-on electron multi-leaf collimator (eMLC) prototype. The measurements were compared against calculations using an electron phase space sampled from a parameterized electron beam model and the voxel Monte Carlo++ (VMC++) code for in-phantom energy deposition. Verification of the calculations was performed in a water phantom with the developed eMLC attached to a Varian 2100 C/D radiotherapy accelerator with nominal energies 6 MeV, 9 MeV, 12 MeV, 16 MeV and 20 MeV. The eMLC prototype consisting of 2 cm thick and 5 mm wide steel leaves is fixed under the 20 x 20 cm(2) electron applicator with a source-to-leaf distance 97.2 cm. The eMLC prototype has non-motorized leaves with straight leaf edges and a maximum field size of 20 x 20 cm(2) at SSD 100 cm. The beam model is a coupled multi-source model with parameters derived from detailed beam characterization measurements and a kernel model for the indirect leaf-scattered electrons. Typical calculation times with a 2% mean statistical uncertainty was under 5 min. In extensive set of in-water measurements 88% of the voxels were within 2% /2 mm acceptance criterion. Although at SSD 100 cm the dose near the phantom surface is slightly pronounced due to the short collimator-to-surface distance, the new beam model was suitable for dose calculation of the add-on type eMLC.