A motion model-guided 4D dose reconstruction for pencil beam scanned proton therapy.

Objective.4D dose reconstruction in proton therapy with pencil beam scanning (PBS) typically relies on a single pre-treatment 4DCT (p4DCT). However, breathing motion during the fractionated treatment can vary considerably in both amplitude and frequency. We present a novel 4D dose reconstruction method combining delivery log files with patient-specific motion models, to account for the dosimetric effect of intra- and inter-fractional breathing variability.Approach.Correlation between an external breathing surrogate and anatomical deformations of the p4DCT is established using principal component analysis. Using motion trajectories of a surface marker acquired during the dose delivery by an optical tracking system, deformable motion fields are retrospectively reconstructed and used to generate time-resolved synthetic 4DCTs ('5DCTs') by warping a reference CT. For three abdominal/thoracic patients, treated with respiratory gating and rescanning, example fraction doses were reconstructed using the resulting 5DCTs and delivery log files. The motion model was validated beforehand using leave-one-out cross-validation (LOOCV) with subsequent 4D dose evaluations. Moreover, besides fractional motion, fractional anatomical changes were incorporated as proof of concept.Main results.For motion model validation, the comparison of 4D dose distributions for the original 4DCT and predicted LOOCV resulted in 3%/3 mm gamma pass rates above 96.2%. Prospective gating simulations on the p4DCT can overestimate the target dose coverage V95%by up to 2.1% compared to 4D dose reconstruction based on observed surrogate trajectories. Nevertheless, for the studied clinical cases treated with respiratory-gating and rescanning, an acceptable target coverage was maintained with V95%remaining above 98.8% for all studied fractions. For these gated treatments, larger dosimetric differences occurred due to CT changes than due to breathing variations.Significance.To gain a better estimate of the delivered dose, a retrospective 4D dose reconstruction workflow based on motion data acquired during PBS proton treatments was implemented and validated, thus considering both intra- and inter-fractional motion and anatomy changes.

Characterization of LiF:Mg,Ti thermoluminescence detectors in low-LET proton beams at ultra-high dose rates.

Objective.This work aims at characterizing LiF:Mg,Ti thermoluminescence detectors (TLDs) for dosimetry of a 250 MeV proton beam delivered at ultra-high dose rates (UHDR). Possible dose rate effects in LiF:Mg,Ti, as well as its usability for dosimetry of narrow proton beams are investigated.Approach.LiF:Mg,Ti (TLD-100TMMicrocubes, 1 mm × 1 mm × 1 mm) was packaged in matrices of 5 × 5 detectors. The center of each matrix was irradiated with single-spot low-LET (energy >244 MeV) proton beam in the (1-4500) Gy s-1average dose rates range. A beam reconstruction procedure was applied to the detectors irradiated at the highest dose rate (Gaussian beam sigma <2 mm) to correct for volumetric averaging effects. Reference dosimetry was carried out with a diamond detector and radiochromic films. The delivered number of protons was measured by a Faraday cup, which was employed to normalize the detector responses.Main results.The lateral beam spread obtained from the beam reconstruction agreed with the one derived from the radiochromic film measurements. No dose rates effects were observed in LiF:Mg,Ti for the investigated dose rates within 3% (k= 1). On average, the dose response of the TLDs agreed with the reference detectors within their uncertainties. The largest deviation (-5%) was measured at 4500 Gy s-1.Significance.The dose rate independence of LiF:Mg,Ti TLDs makes them suitable for dosimetry of UHDR proton beams. Additionally, the combination of a matrix of TLDs and the beam reconstruction can be applied to determine the beam profile of narrow proton beams.

Limitations of phase-sorting based pencil beam scanned 4D proton dose calculations under irregular motion.

Objective.4D dose calculation (4DDC) for pencil beam scanned (PBS) proton therapy is typically based on phase-sorting of individual pencil beams onto phases of a single breathing cycle 4DCT. Understanding the dosimetric limitations and uncertainties of this approach is essential, especially for the realistic treatment scenario with irregular free breathing motion.Approach.For three liver and three lung cancer patient CTs, the deformable multi-cycle motion from 4DMRIs was used to generate six synthetic 4DCT(MRI)s, providing irregular motion (11/15 cycles for liver/lung; tumor amplitudes ∼4-18 mm). 4DDCs for two-field plans were performed, with the temporal resolution of the pencil beam delivery (4-200 ms) or with 8 phases per breathing cycle (500-1000 ms). For the phase-sorting approach, the tumor center motion was used to determine the phase assignment of each spot. The dose was calculated either using the full free breathing motion or individually repeating each single cycle. Additionally, the use of an irregular surrogate signal prior to 4DDC on a repeated cycle was simulated. The CTV volume with absolute dose differences >5% (Vdosediff>5%) and differences in CTVV95%andD5%-D95%compared to the free breathing scenario were evaluated.Main results.Compared to 4DDC considering the full free breathing motion with finer spot-wise temporal resolution, 4DDC based on a repeated single 4DCT resulted inVdosediff>5%of on average 34%, which resulted in an overestimation ofV95%up to 24%. However, surrogate based phase-sorting prior to 4DDC on a single cycle 4DCT, reduced the averageVdosediff>5%to 16% (overestimationV95%up to 19%). The 4DDC results were greatly influenced by the choice of reference cycle (Vdosediff>5%up to 55%) and differences due to temporal resolution were much smaller (Vdosediff>5%up to 10%).Significance.It is important to properly consider motion irregularity in 4D dosimetric evaluations of PBS proton treatments, as 4DDC based on a single 4DCT can lead to an underestimation of motion effects.

Ultra-high dose rate dosimetry for pre-clinical experiments with mm-small proton fields.

PURPOSE: To characterize an experimental setup for ultra-high dose rate (UHDR) proton irradiations, and to address the challenges of dosimetry in millimetre-small pencil proton beams. METHODS: At the PSI Gantry 1, high-energy transmission pencil beams can be delivered to biological samples and detectors up to a maximum local dose rate of âˆ¼9000 Gy/s. In the presented setup, a Faraday cup is used to measure the delivered number of protons up to ultra-high dose rates. The response of transmission ion-chambers, as well as of different field detectors, was characterized over a wide range of dose rates using the Faraday cup as reference. RESULTS: The reproducibility of the delivered proton charge was better than 1 % in the proposed experimental setup. EBT3 films, Al2O3:C optically stimulated luminescence detectors and a PTW microDiamond were used to validate the predicted dose. Transmission ionization chambers showed significant volume ion-recombination (>30 % in the tested conditions) which can be parametrized as a function of the maximum proton current density. Over the considered range, EBT3 films, inorganic scintillator-based screens and the PTW microDiamond were demonstrated to be dose rate independent within ±3 %, ±1.8 % and ±1 %, respectively. CONCLUSIONS: Faraday cups are versatile dosimetry instruments that can be used for dose estimation, field detector characterization and on-line dose verification for pre-clinical experiments in UHDR proton pencil beams. Among the tested detectors, the commercial PTW microDiamond was found to be a suitable option to measure real time the dosimetric properties of narrow pencil proton beams for dose rates up to 2.2 kGy/s.

A static beam delivery device for fast scanning proton arc-therapy.

Arc-therapy is a dose delivery technique regularly applied in photon radiation therapy, and is currently subject of great interest for proton therapy as well. In this technique, proton beams are aimed at a tumor from different continuous ranges of incident directions (so called 'arcs'). This technique can potentially yield a better dose conformity around the tumor and a very low dose in the surrounding healthy tissue. Currently, proton-arc therapy is performed by rotating a proton gantry around the patient, adapting the normally used dose-delivery method to the arc-specific motion of the gantry. Here we present first results from a feasibility study of the conceptual design of a new static fast beam delivery device/system for proton-arc therapy, which could be used instead of a gantry. In this novel concept, the incident angle of proton beams can be set rapidly by only changing field strengths of small magnets. This device eliminates the motion of the heavy gantry and related hardware. Therefore, a reduction of the total treatment time is expected. In the feasibility study presented here, we concentrate on the concept of the beam transport. Based on several simple, but realistic assumptions and approximations, proton tracking calculations were performed in a 3D magnetic field map, to calculate the beam transport in this device and to investigate and address several beam-optics challenges. We propose and simulate corresponding solutions and discuss their outcomes. To enable the implementation of some usually applied techniques in proton therapy, such as pencil beam scanning, energy modulation and beam shaping, we present and discuss our proposals. Here we present the concept of a new idea to perform fast proton arc-scanning and we report on first results of a feasibility study. Based on these results, we propose several options and next steps in the design.

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.

Outcomes, Prognostic Factors and Salvage Treatment for Recurrent Chordoma After Pencil Beam Scanning Proton Therapy at the Paul Scherrer Institute.

AIMS: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS. MATERIALS AND METHODS: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one. RESULTS: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS. CONCLUSION: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.

Pencil Beam Scanning Proton Therapy for Paediatric Neuroblastoma with Motion Mitigation Strategy for Moving Target Volumes.

AIMS: More efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma. MATERIALS AND METHODS: Nineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2-8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation. RESULTS: The mean result of maximum organ motion was 2.7 mm (cranial-caudal), 1.2 mm (left-right), 1.0 mm (anterior-posterior). Four anaesthetised children (21%) showing <5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, -0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7-49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2-4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed. CONCLUSIONS: The early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of <5 mm.

The dependence of interplay effects on the field scan direction in PBS proton therapy.

The literature is controversial about the scan direction dependency of interplay effects in pencil beam scanning (PBS) treatment of moving targets. A directional effect is supported by many simulation studies, whereas the experimental data are mostly limited to simple geometries, not reflecting realistically clinical treatment plans. We have compared increasingly complex treatment fields, from a homogeneous single energy layer to a more modulated lung plan, under identical experimental settings, seeking evidence for differences in motion mitigation due to the selection of primary scanning direction. In total, 120 experimental samples were taken, combining two primary scan directions and three rescanning regimes with different motion scenarios. 4D dose distributions were measured in water with a moving ionisation chamber array and compared to those of a stationary delivery using 2D gamma analysis. Each plan has been verified twice for the same rescanning regime and motion scenario, changing the meandering direction in between to scan perpendicularly to, or along, the target motion. Additionally, machine log files of the lung plan, together with 4DCT data, were used to calculate the dose distribution that such deliveries would have produced in the patient. The primary meandering direction has a clear influence on measured dose distributions when considering a single energy layer. Introducing spot weight modulation and multiple energy layers however, makes the dynamic of interplay more complex and difficult to predict. Overall, gamma (3%/3 mm) differences between scanning along or orthogonal to the target motion follow a normal distribution [Formula: see text] when considering multiple motion scenarios and rescanning regimes. Nevertheless, data spread [Formula: see text] is significant enough such that, for individual experiments and set-ups, a dependency may be observed even if this is not a general result. Patient reconstructed doses follow the same trend, the two primary scan directions producing statistically insignificant differences in dose distributions in terms of conformity or homogeneity. Except for extremely simplified cases of mono-energetic and homogeneous treatment fields, the interplay effect has been found to be only marginally influenced by the choice of the primary scanning direction.

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.

Patient positioning verification for proton therapy using proton radiography.

We present a proof of principle, experimental validation of the potential of proton 'Range Probes' (RP) for patient positioning verification in proton therapy. In this work, we have evaluated experimentally the accuracy of RP by using tissue-like samples and an in-house developed multilayer ionization chamber (MLIC). In addition we build on our previous, simulation based work to present first experimental measurements of RP through anthropomorphic phantoms to detect either rotational or translational positioning errors. For this, a technique has been proposed to characterize the residual integral depth dose curve (RIDDC) after range mixing. This parametrization has been used to evaluate the similarity between Monte Carlo calculated error scenarios of the database and the measured RIDDC, while considering the intrinsic uncertainties of both modalities in order to deduce the positioning error. Finally, the additional dose applied to the patient when using clinical RP with known fluence has been estimated by measuring the local dose of a single RP. In tissue phantoms, the prediction accuracy of the water equivalent path length was 0.70%, with the highest deviations being found in low density samples (up to 5.67%). In addition, the results of the patient positioning verification measurements demonstrated that using carefully selected RPs, 1D translational or rotational errors could be detected with an accuracy of 1 mm and 2°, respectively, and that these would be associated with a low additional dose burden to the patient. In summary, these promising results suggest that the RP method could be a simple, fast and low-dose tool for verifying patient set-up during proton therapy treatment.

Positioning of head and neck patients for proton therapy using proton range probes: a proof of concept study.

To exploit the full potential of proton therapy, accurate and on-line methods to verify the patient positioning and the proton range during the treatment are desirable. Here we propose and validate an innovative technique for determining patient misalignment uncertainties through the use of a small number of low dose, carefully selected proton pencil beams ('range probes') (RP) with sufficient energy that their residual Bragg peak (BP) position and shape can be measured on exit. Since any change of the patient orientation in relation to these beams will result in changes of the density heterogeneities through which they pass, our hypothesis is that patient misalignments can be deduced from measured changes in Bragg curve (BC) shape and range. As such, a simple and robust methodology has been developed that estimates average proton range and range dilution of the detected residual BC, in order to locate range probe positions with optimal prediction power for detecting misalignments. The validation of this RP based approach has been split into two phases. First we retrospectively investigate its potential to detect translational patient misalignments under real clinical conditions. Second, we test it for determining rotational errors of an anthropomorphic phantom that was systematically rotated using an in-house developed high precision motion stage. Simulations of RPs in these two scenarios show that this approach could potentially predict translational errors to lower than1.5 mm and rotational errors to smaller than 1° using only three or five RPs positions respectively.

Contour scanning for penumbra improvement in pencil beam scanned proton therapy.

Proton therapy, especially in the form of pencil beam scanning (PBS), allows for the delivery of highly conformal dose distributions for complex tumor geometries. However, due to scattering of protons inside the patient, lateral dose gradients cannot be arbitrarily steep, which is of importance in cases with organs at risk (OARs) in close proximity to, or overlapping with, planning target volumes (PTVs). In the PBS approach, physical pencil beams are planned using a regular grid orthogonal to the beam direction. In this work, we propose an alternative to this commonly used approach where pencil beams are placed on an irregular grid along concentric paths based on the target contour. Contour driven pencil beam placement is expected to improve dose confirmation by allowing the optimizer to best enhance the penumbra of irregularly shaped targets using edge enhancement. Its effectiveness has been shown to improve dose confirmation to the target volume and reduce doses to OARs in head-and-neck planning studies. Furthermore, the deliverability of such plans, as well as the dosimetric improvements over conventional grid-based plans, have been confirmed in first phantom based verifications.

An anthropomorphic breathing phantom of the thorax for testing new motion mitigation techniques for pencil beam scanning proton therapy.

Motion-induced range changes and incorrectly placed dose spots strongly affect the quality of pencil-beam-scanned (PBS) proton therapy, especially in thoracic tumour sites, where density changes are large. Thus motion-mitigation techniques are necessary, which must be validated in a realistic patient-like geometry. We report on the development and characterisation of a dynamic, anthropomorphic, thorax phantom that can realistically mimic thoracic motions and anatomical features for verifications of proton and photon 4D treatments. The presented phantom is of an average thorax size, and consists of inflatable, deformable lungs surrounded by a skeleton and skin. A mobile 'tumour' is embedded in the lungs in which dosimetry devices (such as radiochromic films) can be inserted. Motion of the tumour and deformation of the thorax is controlled via a custom made pump system driving air into and out of the lungs. Comprehensive commissioning tests have been performed to evaluate the mechanical performance of the phantom, its visibility on CT and MR imaging and its feasibility for dosimetric validation of 4D proton treatments. The phantom performed well on both regular and irregular pre-programmed breathing curves, reaching peak-to-peak amplitudes in the tumour of <20 mm. Some hysteresis in the inflation versus deflation phases was seen. All materials were clearly visualised in CT scans, and all, except the bone and lung components, were MRI visible. Radiochromic film measurements in the phantom showed that imaging for repositioning was required (as for a patient treatment). Dosimetry was feasible with Gamma Index agreements (4%/4 mm) between film dose and planned dose >90% in the central planes of the target. The results of this study demonstrate that this anthropomorphic thorax phantom is suitable for imaging and dosimetric studies in a thoracic geometry closely-matched to lung cancer patients under realistic motion conditions.

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.

Outcomes of patients with non-melanoma solid tumours receiving self-funded pembrolizumab at Chris O'Brien Lifehouse.

BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown. AIM: To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3-4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13-43). Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.

'First, do no harm': managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer.

Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long-term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival-prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.

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.