Technical note: Flat panel proton radiography with a patient specific imaging field for accurate WEPL assessment.

BACKGROUND: Proton radiography (PR) uses highly energetic proton beams to create images where energy loss is the main contrast mechanism. Water-equivalent path length (WEPL) measurements using flat panel PR (FP-PR) have potential for in vivo range verification. However, an accurate WEPL measurement via FP-PR requires irradiation with multiple energy layers, imposing high imaging doses. PURPOSE: A FP-PR method is proposed for accurate WEPL determination based on a patient-specific imaging field with a reduced number of energies (n) to minimize imaging dose. METHODS: Patient-specific FP-PRs were simulated and measured for a head and neck (HN) phantom. An energy selection algorithm estimated spot-wise the lowest energy required to cross the anatomy (Emin) using a water-equivalent thickness map. Starting from Emin, n was restricted to certain values (n = 26, 24, 22, …, 2 for simulations, n = 10 for measurements), resulting in patient-specific FP-PRs. A reference FP-PR with a complete set of energies was compared against patient-specific FP-PRs covering the whole anatomy via mean absolute WEPL differences (MAD), to evaluate the impact of the developed algorithm. WEPL accuracy of patient-specific FP-PRs was assessed using mean relative WEPL errors (MRE) with respect to measured multi-layer ionization chamber PRs (MLIC-PR) in the base of skull, brain, and neck regions. RESULTS: MADs ranged from 2.1 mm (n = 26) to 21.0 mm (n = 2) for simulated FP-PRs, and 7.2 mm for measured FP-PRs (n = 10). WEPL differences below 1 mm were observed across the whole anatomy, except at the phantom surfaces. Measured patient-specific FP-PRs showed good agreement against MLIC-PRs, with MREs of 1.3 ± 2.0%, -0.1 ± 1.0%, and -0.1 ± 0.4% in the three regions of the phantom. CONCLUSION: A method to obtain accurate WEPL measurements using FP-PR with a reduced number of energies selected for the individual patient anatomy was established in silico and validated experimentally. Patient-specific FP-PRs could provide means of in vivo range verification.

Spot scanning proton arc therapy reduces toxicity in oropharyngeal cancer patients.

BACKGROUND: Proton arc technology has recently shown dosimetric gains for various treatment indications. The increased number of beams and energy layers (ELs) in proton arc plans, increases the degrees of freedom in plan optimization and thereby flexibility to spare dose in organs at risk (OARs). A relationship exists between dosimetric plan quality, delivery efficiency, the number of ELs -and beams in a proton arc plan. PURPOSE: This work aims to investigate the effect of the number of beams and ELs in a proton arc plan, on toxicity and delivery time for oropharyngeal cancer patients (OPC) selected for intensity modulated proton therapy (IMPT) based on the Dutch model-based approach. METHODS: The EL reduction algorithm iteratively selects ELs from beams equidistantly spaced over a 360° arc. The beams in the final plan may contain multiple ELs, making them suited for static delivery on the studied treatment machine. The produced plans can therefore be called "step and shoot" proton arc plans. The number of beams and ELs were varied to determine the relationship with the planning cost function value, normal tissue complication probability (NTCP) and delivery time. Proton arc plans with robust target coverage and optimal energy layer reduction (ELR) settings to reduce NTCP, were generated for 10 OPC patients. Proton arc plans were compared to clinical volumetric modulated arc therapy (VMAT) and IMPT plans in terms of integral dose, OAR dose, NTCP for xerostomia and dysphagia and delivery time. Furthermore, dose-weighted average linear energy transfer (LETd ) distributions were compared between the IMPT and proton arc plans. A dry run delivery of a plan containing 20 beams and 360 ELs was performed to evaluate delivery time and accuracy. RESULTS: We found 360 ELs distributed over 30 beams generated proton arc plans with near minimal expected plan toxicity. Relative to corresponding IMPT and VMAT plans, an average reduction of 21 ± 3% and 58 ± 10% in integral dose was observed. D m e a n $_{mean}$ was reduced most in the pharyngeal constrictor muscle (PCM) medius structure, with on average 9.0 ± 4.2 Gy(RBE) (p = 0.0002) compared to the clinical IMPT plans. The average NTCP for grade≥2 and grade≥3 xerostomia at 6 months after treatment significantly decreased with 4.7 ± 1.8% (p = 0.002) and 1.7 ± 0.8% (p = 0.002), respectively, while the average NTCP for grade≥2 and grade≥3 dysphagia decreased with 4.4 ± 2.9% (p = 0.002) and 0.9 ± 0.4% (p = 0.002), respectively, increasing the benefit of protons relative to VMAT. For a "step and shoot" proton arc delivery with auto beam sequencing the estimated delivery time is 11 min, similar to the delivery time of a 6-field IMPT treatment. Gamma analysis between the planned and delivered dose distribution resulted in a 99.99% pass rate using 1mm/1% dose difference/distance to agreement criteria. CONCLUSIONS: "Step and shoot" proton arc demonstrates potential to further reduce toxicity compared to IMPT and VMAT in OPC treatment. By employing 360 ELs and 30 beams in the proposed ELR method, delivery time can reach clinically acceptable levels without compromising plan toxicity when automatic beam sequencing is available.

Proton therapy of a pregnant patient with nasopharyngeal carcinoma.

Background and purpose: Radiotherapy during pregnancy is rarely administered due to lack of data and practical challenges. This is the first detailed report of proton therapy as cancer treatment for a pregnant patient with nasopharyngeal carcinoma. Materials and methods: Pencil beam scanning proton therapy was prescribed to a pregnant patient to a total dose of 70 Gy (RBE) to the therapeutic CTV and 54.25 Gy to the prophylactic CTV, delivered in 35 fractions with a simultaneous integrated boost technique. Results: Phantom measurements showed a thirty-fold decrease in fetal radiation dose when using proton compared to photon therapy, with a total fetal dose of 5.5 mSv for the complete proton treatment, compared to 185 and 298 mSv for the photon treatment with and without lead shielding, respectively. After adminstering proton therapy during pregnancy, at 39 weeks of gestation, a healthy boy with a birthweight on the 83th percentile was delivered. Pediatric follow-up at 2 months of age of the offspring showed normal growth and age-adequate motor development with no signs of neurological problems. MR follow-up of the tumor 3 months after the end of treatment showed complete remission. Conclusion: This case demonstrates the potential of proton therapy for treatment during pregnancy.Compared to photon therapy, proton therapy can significantly limit fetal dose, while simultaneously offering a more optimized treatment to the patient.

Evaluation of robustly optimised intensity modulated proton therapy for nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To evaluate the dosimetric changes occurring over the treatment course for nasopharyngeal carcinoma (NPC) patients treated with robustly optimised intensity modulated proton therapy (IMPT). MATERIALS AND METHODS: 25 NPC patients were treated to two dose levels (CTV1: 70 Gy, CTV2: 54.25 Gy) with robustly optimised IMPT plans. Robustness evaluation was performed over 28 error scenarios using voxel-wise minimum distributions to assess target coverage and voxel-wise maximum distributions to assess possible hotspots and critical organ doses. Daily CBCT was used for positioning and weekly repeat CTs (rCT) were taken, on which the plan dose was recalculated and robustly evaluated. Deformable image registration was used to warp and accumulate the nominal, voxel-wise minimum and maximum rCT dose distributions. Changes to target coverage, critical organ and normal tissue dose between the accumulated and planned doses were investigated. RESULTS: 2 patients required a plan adaptation due to reduced target coverage. The D98% in the accumulated voxel-wise minimum distribution was higher than planned for CTV1 in 24/25 patients and for CTV2 in 20/25 patients. Maximum doses to the critical organs remained acceptable in all patients. Other normal tissue doses showed some variation as a result of soft tissue deformations and weight change. Normal tissue complication probabilities for grade ≥ 2 dysphagia and grade ≥ 2 xerostomia remained similar to planned values. CONCLUSION: Robustly optimised IMPT plans, in combination with volumetric verification imaging and adaptive planning, provided robust target coverage and acceptable OAR dose variation in our NPC cohort when accumulated over longitudinal data.

Optimizing calibration settings for accurate water equivalent path length assessment using flat panel proton radiography.

OBJECTIVE: Proton range uncertainties can compromise the effectiveness of proton therapy treatments. Water equivalent path length (WEPL) assessment by flat panel detector proton radiography (FP-PR) can provide means of range uncertainty detection. Since WEPL accuracy intrinsically relies on the FP-PR calibration parameters, the purpose of this study is to establish an optimal calibration procedure that ensures high accuracy of WEPL measurements. To that end, several calibration settings were investigated. APPROACH: FP-PR calibration datasets were obtained simulating PR fields with different proton energies, directed towards water-equivalent material slabs of increasing thickness. The parameters investigated were the spacing between energy layers (ΔE) and the increment in thickness of the water-equivalent material slabs (ΔX) used for calibration. 30 calibrations were simulated, as a result of combining ΔE = 9, 7, 5, 3, 1 MeV and ΔX = 10, 8, 5, 3, 2, 1 mm. FP-PRs through a CIRS electron density phantom were simulated, and WEPL images corresponding to each calibration were obtained. Ground truth WEPL values were provided by range probing multi-layer ionization chamber simulations on each insert of the phantom. Relative WEPL errors between FP-PR simulations and ground truth were calculated for each insert. Mean relative WEPL errors and standard deviations across all inserts were computed for WEPL images obtained with each calibration. MAIN RESULTS: Large mean and standard deviations were found in WEPL images obtained with large ΔEvalues (ΔE = 9 or 7 MeV), for any ΔX. WEPL images obtained with ΔE ≤ 5 MeV and ΔX ≤ 5 mm resulted in a WEPL accuracy with mean values within ±0.5% and standard deviations around 1%. SIGNIFICANCE: An optimal FP calibration in the framework of this study was established, characterized by 3 MeV ≤ ΔE ≤ 5 MeV and 2 mm ≤ ΔX ≤ 5 mm. Within these boundaries, highly accurate WEPL acquisitions using FP-PR are feasible and practical, holding the potential to assist future online range verification quality control procedures.

Experimental assessment of inter-centre variation in stopping-power and range prediction in particle therapy.

PURPOSE: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. MATERIAL AND METHODS: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. RESULTS: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. CONCLUSION: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion.

Range probing as a quality control tool for CBCT-based synthetic CTs: In vivo application for head and neck cancer patients.

PURPOSE: Cone-beam CT (CBCT)-based synthetic CTs (sCT) produced with a deep convolutional neural network (DCNN) show high image quality, suggesting their potential usability in adaptive proton therapy workflows. However, the nature of such workflows involving DCNNs prevents the user from having direct control over their output. Therefore, quality control (QC) tools that monitor the sCTs and detect failures or outliers in the generated images are needed. This work evaluates the potential of using a range-probing (RP)-based QC tool to verify sCTs generated by a DCNN. Such a RP QC tool experimentally assesses the CT number accuracy in sCTs. METHODS: A RP QC dataset consisting of repeat CTs (rCT), CBCTs, and RP acquisitions of seven head and neck cancer patients was retrospectively assessed. CBCT-based sCTs were generated using a DCNN. The CT number accuracy in the sCTs was evaluated by computing relative range errors between measured RP fields and RP field simulations based on rCT and sCT images. RESULTS: Mean relative range errors showed agreement between measured and simulated RP fields, ranging from -1.2% to 1.5% in rCTs, and from -0.7% to 2.7% in sCTs. CONCLUSIONS: The agreement between measured and simulated RP fields suggests the suitability of sCTs for proton dose calculations. This outcome brings sCTs generated by DCNNs closer toward clinical implementation within adaptive proton therapy treatment workflows. The proposed RP QC tool allows for CT number accuracy assessment in sCTs and can provide means of in vivo range verification.

Development of advanced preselection tools to reduce redundant plan comparisons in model-based selection of head and neck cancer patients for proton therapy.

PURPOSE: In the Netherlands, head and neck cancer (HNC) patients are selected for proton therapy (PT) based on estimated normal tissue complication probability differences (ΔNTCP) between photons and protons, which requires a plan comparison (VMAT vs. IMPT). We aimed to develop tools to improve patient selection for plan comparisons. METHODS: This prospective study consisted of 141 consecutive patients in which a plan comparison was done. IMPT plans of patients not qualifying for PT were classified as 'redundant'. To prevent redundant IMPT planning, 5 methods that were primarily based on regression models were developed to predict IMPT Dmean to OARs, by using data from VMAT plans and volumetric data from delineated targets and OARs. Then, actual and predicted plan comparison outcomes were compared. The endpoint was being selected for proton therapy. RESULTS: Seventy out of 141 patients (49.6%) qualified for PT. Using the developed preselection tools, redundant IMPT planning could have been prevented in 49-68% of the remaining 71 patients not qualifying for PT (=specificity) when the sensitivity of all methods was fixed to 100%, i.e., no false negative cases (positive predictive value range: 57-68%, negative predictive value: 100%). CONCLUSION: The advanced preselection tools, which uses volume and VMAT dose data, prevented labour intensive creation of IMPT plans in up to 68% of non-qualifying patients for PT. No patients qualifying for PT would have been incorrectly denied a plan comparison. This method contributes significantly to a more cost-effective model-based selection of HNC patients for PT.

Technical Note: First report on an in vivo range probing quality control procedure for scanned proton beam therapy in head and neck cancer patients.

PURPOSE: The capability of proton therapy to provide highly conformal dose distributions is impaired by range uncertainties. The aim of this work is to apply range probing (RP), a form of a proton radiography-based quality control (QC) procedure for range accuracy assessment in head and neck cancer (HNC) patients in a clinical setting. METHODS AND MATERIALS: This study included seven HNC patients. RP acquisition was performed using a multi-layer ionization chamber (MLIC). Per patient, two RP frames were acquired within the first two weeks of treatment, on days when a repeated CT scan was obtained. Per RP frame, integral depth dose (IDD) curves of 81 spots around the treatment isocenter were acquired. Range errors are determined as a discrepancy between calculated IDDs in the treatment planning system and measured residual ranges by the MLIC. Range errors are presented relative to the water equivalent path length of individual proton spots. In addition to reporting results for complete measurement frames, an analysis, excluding range error contributions due to anatomical changes, is presented. RESULTS: Discrepancies between measured and calculated ranges are smaller when performing RP calculations on the day-specific patient anatomy rather than the planning CT. The patient-specific range evaluation shows an agreement between calculated and measured ranges for spots in anatomically consistent areas within 3% (1.5 standard deviation). CONCLUSIONS: The results of an RP-based QC procedure implemented in the clinical practice for HNC patients have been demonstrated. The agreement of measured and simulated proton ranges confirms the 3% uncertainty margin for robust optimization. Anatomical variations show a predominant effect on range accuracy, motivating efforts towards the implementation of adaptive radiotherapy.

Composite minimax robust optimization of VMAT improves target coverage and reduces non-target dose in head and neck cancer patients.

BACKGROUND AND PURPOSE: To assess the potential of composite minimax robust optimization (CMRO) compared to planning target volume (PTV)-based optimization for head and neck cancer (HNC) patients treated with volumetric modulated arc therapy (VMAT). MATERIALS AND METHODS: Ten HNC patients previously treated with a PTV-based VMAT plan were studied. In addition to the PTV-plan a VMAT plan was created with CMRO. For both plans an adapted planning strategy was also investigated, including a plan adaptation during the third week of treatment. The PTV-plans and CMRO-plans (adapted and non-adapted) were evaluated by means of the estimated actually given dose (EAGD). Therefore, the dose was calculated on daily acquired CBCTs, mapped onto the planning CT and accumulated. The plans were compared by dosimetric parameters and normal tissue complication probabilities (NTCPs) for tube feeding dependence, grade 2-4 dysphagia and xerostomia. The accuracy of CBCT-based dose accumulation was further quantified by comparisons of dose accumulation on weekly verification CTs. RESULTS: On average, CMRO significantly increased (1.5 Gy) the D98% of the EAGD to the clinical target volume and significantly decreased the mean dose of the ipsilateral parotid (2.8 Gy), inferior pharynx constrictor muscle (0.7 Gy) and the oral cavity (0.8 Gy). This translated into significantly reduced NTCP of tube feeding dependence (0.9%) and xerostomia (2.8%). The differences in EAGD derived from evaluation CTs or CBCTs were minimal. CONCLUSION: Minimax robust optimization led to improved target coverage and dose reduction in organs at risk in HNC patients treated with VMAT.

Effect of different CT scanners and settings on femoral failure loads calculated by finite element models.

In a multi-center patient study, using different CT scanners, CT-based finite element (FE) models are utilized to calculate failure loads of femora with metastases. Previous studies showed that using different CT scanners can result in different outcomes. This study aims to quantify the effects of (i) different CT scanners; (ii) different CT protocols with variations in slice thickness, field of view (FOV), and reconstruction kernel; and (iii) air between calibration phantom and patient, on Hounsfield Units (HU), bone mineral density (BMD), and FE failure load. Six cadaveric femora were scanned on four CT scanners. Scans were made with multiple CT protocols and with or without an air gap between the body model and calibration phantom. HU and calibrated BMD were determined in cortical and trabecular regions of interest. Non-linear isotropic FE models were constructed to calculate failure load. Mean differences between CT scanners varied up to 7% in cortical HU, 6% in trabecular HU, 6% in cortical BMD, 12% in trabecular BMD, and 17% in failure load. Changes in slice thickness and FOV had little effect (≤4%), while reconstruction kernels had a larger effect on HU (16%), BMD (17%), and failure load (9%). Air between the body model and calibration phantom slightly decreased the HU, BMD, and failure loads (≤8%). In conclusion, this study showed that quantitative analysis of CT images acquired with different CT scanners, and particularly reconstruction kernels, can induce relatively large differences in HU, BMD, and failure loads. Additionally, if possible, air artifacts should be avoided. © 2018 Orthopaedic Research Society. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res.

Inter-centre variability of CT-based stopping-power prediction in particle therapy: Survey-based evaluation.

BACKGROUND AND PURPOSE: Stopping-power ratios (SPRs) are used in particle therapy to calculate particle range in patients. The heuristic CT-to-SPR conversion (Hounsfield Look-Up-Table, HLUT), needed for treatment planning, depends on CT-scan and reconstruction parameters as well as the specific HLUT definition. To assess inter-centre differences in these parameters, we performed a survey-based qualitative evaluation, as a first step towards better standardisation of CT-based SPR derivation. MATERIALS AND METHODS: A questionnaire was sent to twelve particle therapy centres (ten from Europe and two from USA). It asked for details on CT scanners, image acquisition and reconstruction, definition of the HLUT, body-region specific HLUT selection, investigations of beam-hardening and experimental validations of the HLUT. Technological improvements were rated regarding their potential to improve SPR accuracy. RESULTS: Scan parameters and HLUT definition varied widely. Either the stoichiometric method (eight centres) or a tissue-substitute-only HLUT definition (three centres) was used. One centre combined both methods. The number of HLUT line segments varied widely between two and eleven. Nine centres had investigated influence of beam-hardening, often including patient-size dependence. Ten centres had validated their HLUT experimentally, with very different validation schemes. Most centres deemed dual-energy CT promising for improving SPR accuracy. CONCLUSIONS: Large inter-centre variability was found in implementation of CT scans, image reconstruction and especially in specification of the CT-to-SPR conversion. A future standardisation would reduce time-intensive institution-specific efforts and variations in treatment quality. Due to the interdependency of multiple parameters, no conclusion can be drawn on the derived SPR accuracy and its inter-centre variability.