Deep learning based uncertainty prediction of deformable image registration for contour propagation and dose accumulation in online adaptive radiotherapy.

Objective.Online adaptive radiotherapy aims to fully leverage the advantages of highly conformal therapy by reducing anatomical and set-up uncertainty, thereby alleviating the need for robust treatments. This requires extensive automation, among which is the use of deformable image registration (DIR) for contour propagation and dose accumulation. However, inconsistencies in DIR solutions between different algorithms have caused distrust, hampering its direct clinical use. This work aims to enable the clinical use of DIR by developing deep learning methods to predict DIR uncertainty and propagating it into clinically usable metrics.Approach.Supervised and unsupervised neural networks were trained to predict the Gaussian uncertainty of a given deformable vector field (DVF). Since both methods rely on different assumptions, their predictions differ and were further merged into a combined model. The resulting normally distributed DVFs can be directly sampled to propagate the uncertainty into contour and accumulated dose uncertainty.Main results.The unsupervised and combined models can accurately predict the uncertainty in the manually annotated landmarks on the DIRLAB dataset. Furthermore, for 5 patients with lung cancer, the propagation of the predicted DVF uncertainty into contour uncertainty yielded for both methods anexpected calibration errorof less than 3%. Additionally, theprobabilisticly accumulated dose volume histograms(DVH) encompass well the accumulated proton therapy doses using 5 different DIR algorithms. It was additionally shown that the unsupervised model can be used for different DIR algorithms without the need for retraining.Significance.Our work presents first-of-a-kind deep learning methods to predict the uncertainty of the DIR process. The methods are fast, yield high-quality uncertainty estimates and are useable for different algorithms and applications. This allows clinics to use DIR uncertainty in their workflows without the need to change their DIR implementation.

Dosimetric comparison of autocontouring techniques for online adaptive proton therapy.

Objective.Anatomical and daily set-up uncertainties impede high precision delivery of proton therapy. With online adaptation, the daily plan is reoptimized on an image taken shortly before the treatment, reducing these uncertainties and, hence, allowing a more accurate delivery. This reoptimization requires target and organs-at-risk (OAR) contours on the daily image, which need to be delineated automatically since manual contouring is too slow. Whereas multiple methods for autocontouring exist, none of them are fully accurate, which affects the daily dose. This work aims to quantify the magnitude of this dosimetric effect for four contouring techniques.Approach.Plans reoptimized on automatic contours are compared with plans reoptimized on manual contours. The methods include rigid and deformable registration (DIR), deep-learning based segmentation and patient-specific segmentation.Main results.It was found that independently of the contouring method, the dosimetric influence of usingautomaticOARcontoursis small (<5% prescribed dose in most cases), with DIR yielding the best results. Contrarily, the dosimetric effect of using theautomatic target contourwas larger (>5% prescribed dose in most cases), indicating that manual verification of that contour remains necessary. However, when compared to non-adaptive therapy, the dose differences caused by automatically contouring the target were small and target coverage was improved, especially for DIR.Significance.The results show that manual adjustment of OARs is rarely necessary and that several autocontouring techniques are directly usable. Contrarily, manual adjustment of the target is important. This allows prioritizing tasks during time-critical online adaptive proton therapy and therefore supports its further clinical implementation.

Patient-specific neural networks for contour propagation in online adaptive radiotherapy.

Objective.fast and accurate contouring of daily 3D images is a prerequisite for online adaptive radiotherapy. Current automatic techniques rely either on contour propagation with registration or deep learning (DL) based segmentation with convolutional neural networks (CNNs). Registration lacks general knowledge about the appearance of organs and traditional methods are slow. CNNs lack patient-specific details and do not leverage the known contours on the planning computed tomography (CT). This works aims to incorporate patient-specific information into CNNs to improve their segmentation accuracy.Approach.patient-specific information is incorporated into CNNs by retraining them solely on the planning CT. The resulting patient-specific CNNs are compared to general CNNs and rigid and deformable registration for contouring of organs-at-risk and target volumes in the thorax and head-and-neck regions.Results.patient-specific fine-tuning of CNNs significantly improves contour accuracy compared to standard CNNs. The method further outperforms rigid registration and a commercial DL segmentation software and yields similar contour quality as deformable registration (DIR). It is additionally 7-10 times faster than DIR.Significance.patient-specific CNNs are a fast and accurate contouring technique, enhancing the benefits of adaptive radiotherapy.

Pediatric emergency room visits for neurological conditions: Description and use of pediatric neurologist advice.

INTRODUCTION AND OBJECTIVE: Information on the spectrum and frequencies of pediatric neurological presentations to emergency departments is vital to optimize quality of care. The objective of this study was to determine the incidence of pediatric neurological emergencies and to analyze the impact of specialist neurological advice in emergency care. PATIENTS AND METHODS: We performed a retrospective descriptive study of pediatric emergency room visits for neurological reasons at the Timone University Hospital in Marseille over a 6-month period (from October 2017 to March 2018). RESULTS: Of the 14,572 emergencies analyzed, 370 (2.5%) were for neurological conditions. These were most commonly seizures (56.7% of cases), headache (19.7%), and motor or sensory deficits (5.1%). The most frequent diagnosis was epileptic seizure (30%), followed by febrile seizure (26.1%) and migraine (15%). Around two in every five patients (37.6%) required hospitalization. Neurological emergencies requiring critical care occurred at a frequency of about one per month (1.6% of cases). A pediatric neurologist was consulted in 37.3% of cases, resulting in a modification of the diagnosis or treatment in 66% of these referrals. CONCLUSION: The results of this study suggest that a formal referral system between the emergency department and pediatric neurologists would be useful.

Update on yesterday's dose-Use of delivery log-files for daily adaptive proton therapy (DAPT).

In daily adaptive proton therapy (DAPT), the treatment plan is re-optimized on a daily basis. It is a straightforward idea to incorporate information from the previous deliveries during the optimization to refine this daily proton delivery. A feedback signal was used to correct for delivery errors and errors from an inaccurate dose calculation used for plan optimization. This feedback signal consisted of a dose distribution calculated with a Monte Carlo algorithm and was based on the spot delivery information from the previous deliveries in the form of log-files. We therefore called the method Update On Yesterday's Dose (UYD). The UYD method was first tested with a simulated DAPT treatment and second with dose measurements using an anthropomorphic phantom. For both, the simulations and the measurements, a better agreement between the delivered and the intended dose distribution could be observed using UYD. Gamma pass rates (1%/1 mm) increased from around 75% to above 90%, when applying the closed-loop correction for the simulations, as well as the measurements. For a DAPT treatment, positioning errors or anatomical changes are incorporated during the optimization and therefore are less dominant in the overall dose uncertainty. Hence, the relevance of algorithm or delivery machine errors even increases compared to standard therapy. The closed-loop process described here is a method to correct for these errors, and potentially further improve DAPT.

Assessing the advantages of CFR-PEEK over titanium spinal stabilization implants in proton therapy-a phantom study.

High-density materials, such as titanium, used for spinal stabilization, introduces several critical issues in proton therapy (PT). Artefacts affect both contouring and dose calculation. Subsequently, artefacts need to be corrected which is a time-consuming process. Besides, titanium causes proton interactions that are unaccounted for in dose calculation. The result is a suboptimal treatment plan, and indeed decreased local controls have been reported for these patients. Carbon fiber reinforced polyetheretherketone (CFR-PEEK) implant material, which is of low density, potentially solves these issues. For this study, we designed a unique phantom to compare the effects of titanium and CFR-PEEK implants in PT. The phantom contains four interchangeable spinal inserts representing a native spine, and three different spinal stabilizations consisting of titanium only, CFR-PEEK only, and a combination of titanium and CFR-PEEK. All phantom scenarios received the standard treatment workup. Two planning approaches were investigated: a single field plan and a multi-field optimized plan with spinal cord sparing. For both plans we analyzed the following aspects: total volume of artefacts on CT images, time required for artefact correction, effect of planning CT correction on dose calculation, plan robustness to range and set up uncertainties, and finally the discrepancy between the calculated dose and the delivered dose with Gafchromic® film. The CFR-PEEK implant had a 90% reduction of artefacts on CT images and subsequently severely reduced the time for artefact correction with respect to the titanium-only implant. Furthermore, the CFR-PEEK as opposed to titanium did not influence the robustness of the plan. Finally, the titanium implants led to hardware-related discrepancies between the planned and the measured dose while the CFR-PEEK implant showed good agreement. As opposed to titanium, CFR-PEEK has none to minor effects on PT. The use of CFR-PEEK is expected to optimize treatment and possibly improve outcomes for patients that require spinal stabilization.

Two cases of fractures in neonates associated with maternofetal vitamin D deficiency.

Vitamin D supplementation is essential for the entire population, especially during pregnancy and in the pediatric period. We report two case studies of full-term newborns who presented long-bone fractures associated with severe vitamin D deficiency transmitted to them by their mothers, even though maternal supplementation had been implemented according to the existing recommendations. These observations encourage the investigation of neonatal vitamin D deficiency in the presence of long-bone fractures in the absence of traumatic birth and the necessity of reenforcing the means of prevention and the selection of risk groups in order to adjust vitamin D supplementation during pregnancy individually.

Alternatives to patient specific verification measurements in proton therapy: a comparative experimental study with intentional errors.

Patient specific verification (PSV) measurements for pencil beam scanning (PBS) proton therapy are resource-consuming and necessitate substantial beam time outside of clinical hours. As such, efforts to safely reduce the PSV-bottleneck in the clinical work-flow are of great interest. Here, capabilities of current PSV methods to ensure the treatment integrity were investigated and compared to an alternative approach of reconstructing the dose distribution directly from the machine control- or delivery log files with the help of an independent dose calculation (IDC). Scenarios representing a wide range of delivery or work-flow failures were identified (e.g. error in spot position, air gap or pre-absorber setting) and machine files were altered accordingly. This yielded 21 corrupted treatment files, which were delivered and measured with our clinical PSV protocol. IDC machine- and log file checks were also conducted and their sensitivity at detecting the errors compared to the measurements. Although some of the failure scenarios induced clinically relevant dose deviations in the patient geometry, the PSV measurement protocol only detected one out of 21 error scenarios. However, 11 and all 21 error scenarios were detected using dose reconstructions based on the log and machine files respectively. Our data suggests that, although commonly used in particle therapy centers, PSV measurements do a poor job detecting data transfer failures and imperfect delivery machine performance. Machine- and log-file IDCs have been shown to successfully detect erroneous work-flows and to represent a reliable addition to the QA procedure, with the potential to replace PSV.

Factors influencing the performance of patient specific quality assurance for pencil beam scanning IMPT fields.

PURPOSE: A detailed analysis of 2728 intensity modulated proton therapy (IMPT) fields that were clinically delivered to patients between 2007 and 2013 at Paul Scherrer Institute (PSI) was performed. The aim of this study was to analyze the results of patient specific dosimetric verifications and to assess possible correlation between the quality assurance (QA) results and specific field metrics. METHODS: Dosimetric verifications were performed for every IMPT field prior to patient treatment. For every field, a steering file was generated containing all the treatment unit information necessary for treatment delivery: beam energy, beam angle, dose, size of air gap, nuclear interaction (NI) correction factor, number of range shifter plates, number of Bragg peaks (BPs) with their position and weight. This information was extracted and correlated to the results of dosimetric verification of each field which was a measurement of two orthogonal profiles using an orthogonal ionization chamber array in a movable water column. RESULTS: The data analysis has shown more than 94% of all verified plans were within defined clinical tolerances. The differences between measured and calculated dose depend critically on the number of BPs, total thickness of all range shifter plates inserted in the beam path, and maximal range. An increase of the dose difference was observed with smaller number of BPs (i.e., smaller tumor) and smaller ranges (i.e., superficial tumors). The results of the verification do not depend, however, on the prescribed dose, NI correction, or the size of the air gap. There is no dependency of the transversal and longitudinal spot position precision on the beam angle. The value of NI correction depends on the number of spots and number of range shifter plates. CONCLUSIONS: The presented study has shown that the verification method used at Centre for Proton Therapy at Paul Scherrer Institute is accurate and reproducible for performing patient specific QA. The results confirmed that the dose discrepancy is dependent on the size and location of the tumor.

Influence of the transition width on the magnetocaloric effect across the magnetostructural transition of Heusler alloys.

We report a complete structural and magneto-thermodynamic characterization of four samples of the Heusler alloy Ni-Co-Mn-Ga-In, characterized by similar compositions, critical temperatures and high inverse magnetocaloric effect across their metamagnetic transformation, but different transition widths. The object of this study is precisely the sharpness of the martensitic transformation, which plays a key role in the effective use of materials and which has its origin in both intrinsic and extrinsic effects. The influence of the transition width on the magnetocaloric properties has been evaluated by exploiting a phenomenological model of the transformation built through geometrical considerations on the entropy versus temperature curves. A clear result is that a large temperature span of the transformation is unfavourable to the magnetocaloric performance of a material, reducing both isothermal entropy change and adiabatic temperature change obtainable in a given magnetic field and increasing the value of the maximum field needed to fully induce the transformation. The model, which is based on standard magnetometric and conventional calorimetric measurements, turns out to be a convenient tool for the determination of the optimum values of transformation temperature span in a trade-off between sheer performance and amplitude of the operating range of a material.This article is part of the themed issue 'Taking the temperature of phase transitions in cool materials'.

Assessing the quality of proton PBS treatment delivery using machine log files: comprehensive analysis of clinical treatments delivered at PSI Gantry 2.

Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within +/- 1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow. In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field.

Lorentz microscopy sheds light on the role of dipolar interactions in magnetic hyperthermia.

Monodispersed Fe3O4 nanoparticles with comparable size distributions have been synthesized by two different synthesis routes, co-precipitation and thermal decomposition. Thanks to the different steric stabilizations, the described samples can be considered as a model system to investigate the effects of magnetic dipolar interactions on the aggregation states of the nanoparticles. Moreover, the presence of magnetic dipolar interactions can strongly affect the nanoparticle efficiency as a hyperthermic mediator. In this paper, we present a novel way to visualize and map the magnetic dipolar interactions in different kinds of nanoparticle aggregates by the use of Lorentz microscopy, an easy and reliable in-line electron holographic technique. By exploiting Lorentz microscopy, which is complementary to the magnetic measurements, it is possible to correlate the interaction degrees of magnetic nanoparticles with their magnetic behaviors. In particular, we demonstrate that Lorentz microscopy is successful in visualizing the magnetic configurations stabilized by dipolar interactions, thus paving the way to the comprehension of the power loss mechanisms for different nanoparticle aggregates.

Defining robustness protocols: a method to include and evaluate robustness in clinical plans.

We aim to define a site-specific robustness protocol to be used during the clinical plan evaluation process. Plan robustness of 16 skull base IMPT plans to systematic range and random set-up errors have been retrospectively and systematically analysed. This was determined by calculating the error-bar dose distribution (ebDD) for all the plans and by defining some metrics used to define protocols aiding the plan assessment. Additionally, an example of how to clinically use the defined robustness database is given whereby a plan with sub-optimal brainstem robustness was identified. The advantage of using different beam arrangements to improve the plan robustness was analysed. Using the ebDD it was found range errors had a smaller effect on dose distribution than the corresponding set-up error in a single fraction, and that organs at risk were most robust to the range errors, whereas the target was more robust to set-up errors. A database was created to aid planners in terms of plan robustness aims in these volumes. This resulted in the definition of site-specific robustness protocols. The use of robustness constraints allowed for the identification of a specific patient that may have benefited from a treatment of greater individuality. A new beam arrangement showed to be preferential when balancing conformality and robustness for this case. The ebDD and error-bar volume histogram proved effective in analysing plan robustness. The process of retrospective analysis could be used to establish site-specific robustness planning protocols in proton therapy. These protocols allow the planner to determine plans that, although delivering a dosimetrically adequate dose distribution, have resulted in sub-optimal robustness to these uncertainties. For these cases the use of different beam start conditions may improve the plan robustness to set-up and range uncertainties.

Controlled co-deposition of FePt nanoparticles embedded in MgO: a detailed investigation of structure and electronic and magnetic properties.

Films of FePt nanoparticles (NPs) embedded in MgO were obtained by controlled co-deposition of FePt NPs pre-formed by a gas aggregation source and of Mg evaporated in an oxygen atmosphere. Assemblies of core-shell FePt@MgO NPs and films of FePt NPs embedded in MgO matrix could be obtained by varying FePt and Mg deposition rates. Transmission electron microscopy (TEM) and high resolution-TEM revealed the core-shell structure of the NPs, with an FePt core (of average diameter (d) = 4.75 nm) presenting a multitwinned icosahedral structure, and MgO partially in crystalline form. The functional effect of the MgO shell in shielding the FePt core from external oxidation was shown with XPS. Upon controlled annealing, a transition from A1 to L10 ordering could be obtained, with structural and morphological re-arrangement. The magnetic hysteresis loops obtained from alternating gradient field magnetometry at room temperature show a 'wasp-waist' shape, with small values of coercive field (Hc = 300-1400 Oe), decreasing at increasing amounts of co-deposited MgO.

Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms.

PURPOSE: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). PATIENTS AND METHODS: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81%), sarcomas (16%) and meningiom (3%). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. RESULTS: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm(3). A mean of 93.2% of the PTV was covered by at least 90% of the prescribed dose. SB volumes (cm(3)) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5=0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of >70 Gy (RBE), SB received >50 and >60 Gy (RBE) in only 61 and 54% of patients, respectively. Mean SB volumes (cm(3)) covered by different dose levels (Gy, RBE) were: V20 (n=24): 45.1, V50 (n=19): 17.7, V60 (n=17): 7.6 and V70 (n=12): 2.4. No acute toxicity ≥ grade 2 or late SB sequelae were observed. CONCLUSION: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology.

Composite multifunctional nanostructures based on ZnO tetrapods and superparamagnetic Fe3O4 nanoparticles.

A nanocomposite material is obtained by coupling superparamagnetic magnetite nanoparticles (Fe3O4 NP) and vapor phase grown zinc oxide nanostructures with 'tetrapod' morphology (ZnO TP). The aim is the creation of a multifunctional material which retains the attractive features of ZnO (e.g. surface reactivity, strong UV emission, piezoelectricity) together with added magnetism. Structural, morphological, optical, magnetic and functional characterization are performed. In particular, the high saturation magnetization of Fe3O4 NP (above 50 A m(2) kg(-1)), the strong UV luminescence and the enhanced photocatalytic activity of coupled nanostructures are discussed. Thus the nanocomposite turns out to be suitable for applications in energy harvesting and conversion, gas- and bio-sensing, bio-medicine and filter-free photocatalysis.

Advantages and limitations of the 'worst case scenario' approach in IMPT treatment planning.

The 'worst case scenario' (also known as the minimax approach in optimization terms) is a common approach to model the effect of delivery uncertainties in proton treatment planning. Using the 'dose-error-bar distribution' previously reported by our group as an example, we have investigated in more detail one of the underlying assumptions of this method. That is, the dose distributions calculated for a limited number of worst case patient positioning scenarios (i.e. limited number of shifts sampled on a spherical surface) represent the worst dose distributions that can occur during the patient treatment under setup uncertainties. By uniformly sampling patient shifts from anywhere within a spherical error-space, a number of treatment scenarios have been simulated and dose deviations from the nominal dose distribution have been computed. The dose errors from these simulations (comprehensive approach) have then been compared to the dose-error-bar approach previously reported (surface approximation) using both point-by-point and dose- and error-volume-histogram analysis (DVH/EVHs). This comparison has been performed for two different clinical cases treated using intensity modulated proton therapy (IMPT): a skull-base and a spinal-axis tumor. Point-by-point evaluation shows that the surface approximation leads to a correct estimation (95% accuracy) of the potential dose errors for the 96% and 85% of the irradiated voxels, for the two investigated cases respectively. We also found that the voxels for which the surface approximation fails are generally localized close to sharp soft tissue-bone interfaces and air cavities. Moreover, analysis of EVHs and DVHs for the two cases shows that the percentage of voxels of a given volume of interest potentially affected by a certain maximum dose error is correctly estimated using the surface approximation and that this approach also accurately predicts the upper and lower bounds of the DVH curves that can occur under positioning uncertainties. In conclusion, the assumption that the larger the patient shift the worse the dose error does not always hold on a point-by-point basis. Nevertheless, when performing a volumetric analysis, a limited set of worst case error scenarios correctly represents the worst quality of the plan in presence of setup errors. As a consequence of these results, we believe that the worst case scenario approach can be used in the IMPT planning procedure for estimating plan robustness provided that the possible limitations of this approach are known.

Is it necessary to plan with safety margins for actively scanned proton therapy?

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.

Experimental verification of IMPT treatment plans in an anthropomorphic phantom in the presence of delivery uncertainties.

Clinically relevant intensity modulated proton therapy (IMPT) treatment plans were measured in a newly developed anthropomorphic phantom (i) to assess plan accuracy in the presence of high heterogeneity and (ii) to measure plan robustness in the case of treatment uncertainties (range and spatial). The new phantom consists of five different tissue substitute materials simulating different tissue types and was cut into sagittal planes so as to facilitate the verification of co-planar proton fields. GafChromic films were positioned in the different planes of the phantom, and 3D-IMPT and distal edge tracking (DET) plans were delivered to a volume simulating a skull base chordoma. In addition, treatments planned on CTs of the phantom with HU units modified were delivered to simulate systematic range uncertainties (range-error treatments). Finally, plans were delivered with the phantom rotated to simulate spatial errors. Results show excellent agreement between the calculated and the measured dose distribution: >99% and 98% of points with a gamma value <1 (3%/3 mm) for the 3D-IMPT and the DET plan, respectively. For both range and spatial errors, the 3D-IMPT plan was more robust than the DET plan. Both plans were more robust to range than to the spatial uncertainties. Finally, for range error treatments, measured distributions were compared to a model for predicting delivery errors in the treatment planning system. Good agreement has been found between the model and the measurements for both types of IMPT plan.

The influence of the optimization starting conditions on the robustness of intensity-modulated proton therapy plans.

In this paper the influence of varying the starting conditions on intensity-modulated proton therapy (IMPT) plans has been studied. In particular IMPT plans have been optimized based on four different starting conditions of initial beamlet fluences: (a) all beamlets with an initial constant weight, delivering a gradient from the proximal to the distal edge of the target (forward wedge approach); (b) beamlet weights reduced from the distal to the proximal aspect of the target such as to deliver a flat 'spread-out-Bragg-peak' (SOBP approach); (c) beamlet weights calculated to deliver a gradient from the distal (maximal dose) to the proximal edge (inverse wedge); (d) beamlet weights set universally to zero except the most distal one, for each given lateral direction (i.e. distal-edge-tracking, DET). An analysis of robustness to range errors has been performed by recalculating plans, assuming a systematic 3% error in CT values. Results showed that IMPT plans optimized with the forward wedge approach were very sensitive to range errors, since organs-at-risk (OAR) were spared by patching single-field lateral and distal fall-offs, the last ones being strongly sensitive to range errors. In addition a plan robust to range errors can be achieved by starting the optimization process in the case of low-dose constraints to OAR, with the initial flat SOBP approach, and with either the DET or the inverse wedge approaches, in the case of stringent dose-volume constraints to OAR. 'Starting condition-based optimization' as proposed here can therefore provide a tool to transparently 'steer' the optimization outcome to solutions more robust to uncertainties.