Early outcome after craniospinal irradiation with pencil beam scanning proton therapy for children, adolescents and young adults with brain tumors.

Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4 years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n = 42: 59%) and ependymoma (n = 8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54 GyRBE (range: 18-60.4), and median prescribed craniospinal dose was 24 GyRBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5 months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2 years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT.

Advances in radiotherapy technology for pediatric cancer patients and roles of medical physicists: COG and SIOP Europe perspectives.

Over the last two decades, rapid technological advances have dramatically changed radiation delivery to children with cancer, enabling improved normal-tissue sparing. This article describes recent advances in photon and proton therapy technologies, image-guided patient positioning, motion management, and adaptive therapy that are relevant to pediatric cancer patients. For medical physicists who are at the forefront of realizing the promise of technology, challenges remain with respect to ensuring patient safety as new technologies are implemented with increasing treatment complexity. The contributions of medical physicists to meeting these challenges in daily practice, in the conduct of clinical trials, and in pediatric oncology cooperative groups are highlighted. Representing the perspective of the physics committees of the Children's Oncology Group (COG) and the European Society for Paediatric Oncology (SIOP Europe), this paper provides recommendations regarding the safe delivery of pediatric radiotherapy. Emerging innovations are highlighted to encourage pediatric applications with a view to maximizing the therapeutic ratio.

Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy.

BACKGROUND: The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39 years) with brain/skull base tumors treated with pencil beam scanning proton therapy. METHODS: One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30 years (range 15-39) and median prescribed dose was 70.0 Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). RESULTS: After a median follow up of 66 months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. CONCLUSIONS: PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.

Characterization of a Low-Cost Plastic Fiber Array Detector for Proton Beam Dosimetry.

The Pencil Beam Scanning (PBS) technique in proton therapy uses fast magnets to scan the tumor volume rapidly. Changing the proton energy allows changing to layers in the third dimension, hence scanning the same volume several times. The PBS approach permits adapting the speed and/or current to modulate the delivered dose. We built a simple prototype that measures the dose distribution in a single step. The active detection material consists of a single layer of scintillating fibers (i.e., 1D) with an active length of 100 mm, a width of 18.25 mm, and an insignificant space (20 µm) between them. A commercial CMOS-based camera detects the scintillation light. Short exposure times allow running the camera at high frame rates, thus, monitoring the beam motion. A simple image processing method extracts the dose information from each fiber of the array. The prototype would allow scaling the concept to multiple layers read out by the same camera, such that the costs do not scale with the dimensions of the fiber array. Presented here are the characteristics of the prototype, studied under two modalities: spatial resolution, linearity, and energy dependence, characterized at the Center for Proton Therapy (Paul Scherrer Institute); the dose rate response, measured at an electron accelerator (Swiss Federal Institute of Metrology).

Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates.

Background: This study aimed at evaluating spatially varying instantaneous dose rates for different intensity-modulated proton therapy (IMPT) planning strategies and delivery scenarios, and comparing these with FLASH dose rates (>40 Gy/s). Material and methods: In order to quantify dose rates in three-dimensions, we proposed the 'dose-averaged dose rate' (DADR) metric, defined for each voxel as the dose-weighted mean of the instantaneous dose rates of all spots (i.e., pencil beams). This concept was applied to four head-and-neck cases, each planned with clinical (4 fields) and various spot-reduced IMPT techniques: 'standard' (4 fields), 'arc' (120 fields) and 'arc-shoot-through' (120 fields; 229 MeV only). For all plans, different delivery scenarios were simulated: constant beam intensity, variable beam intensity for a clinical Varian ProBeam system, varied per energy layer or per spot, and theoretical spot-wise variable beam intensity (i.e., no monitor/safety limitations). DADR distributions were calculated assuming 2-Gy or 6-Gy fractions. Results: Spot-reduced plans contained 17-52 times fewer spots than clinical plans, with no deterioration of plan quality. For the clinical plans, the mean DADR in normal tissue for 2-Gy fractionation was 1.7 Gy/s (median over all patients) at maximum, whereas in standard spot-reduced plans it was 0.7, 4.4, 7.1, and 12.1 Gy/s, for the constant, energy-layer-wise, spot-wise, and theoretical spot-wise delivery scenarios, respectively. Similar values were observed for arc plans. Arc-shoot-through planning resulted in DADR values of 3.0, 6.0, 14.1, and 24.4 Gy/s, for the abovementioned scenarios. Hypofractionation (3×) generally resulted in higher dose rates, up to 73.2 Gy/s for arc-shoot-through plans. The DADR was inhomogeneously distributed with highest values at beam entrance and at the Bragg peak. Conclusion: FLASH dose rates were not achieved for conventional planning and clinical spot-scanning machines. As such, increased spot-wise beam intensities, spot-reduced planning, hypofractionation and arc-shoot-through plans were required to achieve FLASH compatible dose rates.

Daily adaptive proton therapy - the key to innovative planning approaches for paranasal cancer treatments.

Background: For proton therapy of paranasal tumors, field directions avoiding volumes that might change during therapy are typically used. If the plan is optimized on the daily anatomy using daily adapted proton therapy (DAPT) however, field directions crossing the nasal cavities might be feasible. In this study, we investigated the effectiveness of DAPT for enabling narrow-field treatment approaches. Material and methods: For five paranasal tumor patients, representing a wide patient spectrum, anatomically robust 4-field-star and narrow-field plans were calculated and their robustness to anatomical and setup uncertainties was compared with and without DAPT. Based on the nominal planning CTs, per patient up to 125 simulated CTs (simCTs) with different nasal cavity fillings were created and random translations and rotations due to patient setup uncertainties were further simulated. Plans were recalculated or re-optimized on all error scenarios, representing non-adapted and DAPT fractions, respectively. From these, 100 possible treatments (60 GyRBE, 30 fx) were simulated and changes in integral dose, target and organs at risk (OARs) doses evaluated. Results: In comparison to the 4-field-star approach, the use of narrow-fields reduced integral dose between 29% and 56%. If OARs did not overlap with the target, OAR doses were also reduced. Finally, the significantly reduced target coverage in non-adapted treatments (mean V95 reductions of up to 34%) could be almost fully restored with DAPT in all cases (differences <1%). Conclusions: DAPT was found to be not only an effective way to increase plan robustness to anatomical and positional uncertainties, but also opened the possibility to use improved and more conformal field arrangements.

Intensity modulated proton therapy plan generation in under ten seconds.

Background: Treatment planning for intensity modulated proton therapy (IMPT) can be significantly improved by reducing the time for plan calculation, facilitating efficient sampling of the large solution space characteristic of IMPT treatments. Additionally, fast plan generation is a key for online adaptive treatments, where the adapted plan needs to be ideally available in a few seconds. However, plan generation is a computationally demanding task and, although dose restoration methods for adaptive therapy have been proposed, computation times remain problematic. Material and methods: IMPT plan generation times were reduced by the development of dedicated graphical processing unit (GPU) kernels for our in-house, clinically validated, dose and optimization algorithms. The kernels were implemented into a coherent system, which performed all steps required for a complete treatment plan generation. Results: Using a single GPU, our fast implementation was able to generate a complete new treatment plan in 5-10 sec for typical IMPT cases, and in under 25 sec for plans to very large volumes such as for cranio-spinal axis irradiations. Although these times did not include the manual input of optimization parameters or a final clinical dose calculation, they included all required computational steps, including reading of CT and beam data. In addition, no compromise was made on plan quality. Target coverage and homogeneity for four patient plans improved (by up to 6%) or remained the same (changes <1%). No worsening of dose-volume parameters of the relevant organs at risk by more than 0.5% was observed. Conclusions: Fast plan generation with a clinically validated dose calculation and optimizer is a promising approach for daily adaptive proton therapy, as well as for automated or highly interactive planning.

Pencil beam scanned protons for the treatment of patients with Ewing sarcoma.

BACKGROUND: Few data exist regarding the clinical outcome of patients with Ewing sarcoma (EWS) treated with pencil beam scanning proton therapy (PT). We report the outcome of children, adolescents and young adults (AYA) treated with PT at the Paul Scherrer Institute. MATERIALS: Thirty-eight patients (median age, 9.9 years) received a median dose of 54.9 Gy(RBE) (where RBE is relative biologic effectiveness). Size of the tumor ranged from 1.7 to 24 cm. Most common primary site was axial/pelvic (n = 27; 71%). Four patients (11%) presented with metastases at diagnosis. Twenty (53%) patients had chemo-PT only. Median follow-up was 49.6 months (range, 9.2-131.7). RESULTS: The 5-year actuarial rate of local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were 81.5%, 76.4%, and 83.0%, respectively. All local recurrences occurred in field and in patients with nonextremity primaries. Six patients died, all of tumor progression. Age < 10 years was a favorable factor of borderline significance for LC (P = 0.05) and OS (P = 0.05), but was significant for DMFS (P = 0.003). Tumor volume <200 ml was a significant prognostic factors for DMFS (P = 0.03), but not for OS (P = 0.07). Metastasis at diagnosis was a strong predictor of local failure (P = 0.003). Only two grade 3 late toxicities were observed. The 5-year actuarial rate of grade 3 toxicity-free survival was 90.9%. CONCLUSIONS: These preliminary data suggest that the outcomes of children and AYA with EWS are good and PT was well tolerated with few late adverse events. The local and distant tumor control for older patients with large pre-PT tumor volumes remains problematic.

Impact of beam angle choice on pencil beam scanning breath-hold proton therapy for lung lesions.

INTRODUCTION: The breath-hold technique inter alia has been suggested to mitigate the detrimental effect of motion on pencil beam scanned (PBS) proton therapy dose distributions. The aim of this study was to evaluate the robustness of incident proton beam angles to day-to-day anatomical variations in breath-hold. MATERIALS AND METHODS: Single field PBS plans at five degrees increments in the transversal plane were made and water-equivalent path lengths (WEPLs) were derived on the planning breath-hold CT (BHCT) for 30 patients diagnosed with locally-advanced non-small cell lung cancer (NSCLC), early stage NSCLC or lung metastasis. Our treatment planning system was subsequently used to recalculate the plans and derive WEPL on a BHCT scan acquired at the end of the treatment. Changes to the V95%, D95 and mean target dose were evaluated. RESULTS: The difference in WEPL as a function of the beam angle was highly patient specific, with a median of 3.3 mm (range: 0.0-41.1 mm). Slightly larger WEPL differences were located around the lateral or lateral anterior/posterior beam angles. Linear models revealed that changes in dose were associated to the changes in WEPL and the tumor baseline shift (p < 0.05). CONCLUSIONS: WEPL changes and tumor baseline shift can serve as reasonable surrogates for dosimetric uncertainty of the target coverage and are well-suited for routine evaluation of plan robustness. The two lateral beam angles are not recommended to use for PBS proton therapy of lung cancer patients treated in breath-hold, due to the poor robustness for several of the patients evaluated.

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute.

BACKGROUND: Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES: Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS: With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS: Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

The impact of motion on onboard MRI-guided pencil beam scanned proton therapy treatments.

Objective.Online magnetic resonance imaging (MRI) guidance could be especially beneficial for pencil beam scanned (PBS) proton therapy of tumours affected by respiratory motion. For the first time to our knowledge, we investigate the dosimetric impact of respiratory motion on MRI-guided proton therapy compared to the scenario without magnetic field.Approach.A previously developed analytical proton dose calculation algorithm accounting for perpendicular magnetic fields was extended to enable 4D dose calculations. For two geometrical phantoms and three liver and two lung patient cases, static treatment plans were optimised with and without magnetic field (0, 0.5 and 1.5 T). Furthermore, plans were optimised using gantry angle corrections (0.5 T +5° and 1.5 T +15°) to reproduce similar beam trajectories compared to the 0 T reference plans. The effect of motion was then considered using 4D dose calculations without any motion mitigation and simulating 8-times volumetric rescanning, with motion for the patient cases provided by 4DCT(MRI) data sets. Each 4D dose calculation was performed for different starting phases and the CTV dose coverageV95%and homogeneityD5%-D95%were analysed.Main results.For the geometrical phantoms with rigid motion perpendicular to the beam and parallel to the magnetic field, a comparable dosimetric effect was observed independent of the magnetic field. Also for the five 4DCT(MRI) cases, the influence of motion was comparable for all magnetic field strengths with and without gantry angle correction. On average, the motion-induced decrease in CTVV95%from the static plan was 17.0% and 18.9% for 1.5 T and 0.5 T, respectively, and 19.9% without magnetic field.Significance.For the first time, this study investigates the combined impact of magnetic fields and respiratory motion on MR-guided proton therapy. The comparable dosimetric effects irrespective of magnetic field strength indicate that the effects of motion for future MR-guided proton therapy may not be worse than for conventional PBS proton therapy.

Automatic lung segmentation of magnetic resonance images: A new approach applied to healthy volunteers undergoing enhanced Deep-Inspiration-Breath-Hold for motion-mitigated 4D proton therapy of lung tumors.

Background and purpose: Respiratory suppression techniques represent an effective motion mitigation strategy for 4D-irradiation of lung tumors with protons. A magnetic resonance imaging (MRI)-based study applied and analyzed methods for this purpose, including enhanced Deep-Inspiration-Breath-Hold (eDIBH). Twenty-one healthy volunteers (41-58 years) underwent thoracic MR scans in four imaging sessions containing two eDIBH-guided MRIs per session to simulate motion-dependent irradiation conditions. The automated MRI segmentation algorithm presented here was critical in determining the lung volumes (LVs) achieved during eDIBH. Materials and methods: The study included 168 MRIs acquired under eDIBH conditions. The lung segmentation algorithm consisted of four analysis steps: (i) image preprocessing, (ii) MRI histogram analysis with thresholding, (iii) automatic segmentation, (iv) 3D-clustering. To validate the algorithm, 46 eDIBH-MRIs were manually contoured. Sørensen-Dice similarity coefficients (DSCs) and relative deviations of LVs were determined as similarity measures. Assessment of intrasessional and intersessional LV variations and their differences provided estimates of statistical and systematic errors. Results: Lung segmentation time for 100 2D-MRI planes was âˆ¼ 10 s. Compared to manual lung contouring, the median DSC was 0.94 with a lower 95 % confidence level (CL) of 0.92. The relative volume deviations yielded a median value of 0.059 and 95 % CLs of -0.013 and 0.13. Artifact-based volume errors, mainly of the trachea, were estimated. Estimated statistical and systematic errors ranged between 6 and 8 %. Conclusions: The presented analytical algorithm is fast, precise, and readily available. The results are comparable to time-consuming, manual segmentations and other automatic segmentation approaches. Post-processing to remove image artifacts is under development.

Treatment planning comparison for head and neck cancer between photon, proton, and combined proton-photon therapy - From a fixed beam line to an arc.

BACKGROUND AND PURPOSE: This study investigates whether combined proton-photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments. MATERIAL AND METHODS: Five HNC patients with a planning CT and multiple (4-7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared. RESULTS: The target coverage for CPPT without adaptation is insufficient (average V95%=88.4 %), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5 %) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are -2.7 %/-3.4 %/-5.0 % for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are + 0.8 %/-0.9 %/-4.3 %. CONCLUSION: CPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined.

Uncertainty-aware MR-based CT synthesis for robust proton therapy planning of brain tumour.

BACKGROUND AND PURPOSE: Deep learning techniques excel in MR-based CT synthesis, but missing uncertainty prediction limits its clinical use in proton therapy. We developed an uncertainty-aware framework and evaluated its efficiency in robust proton planning. MATERIALS AND METHODS: A conditional generative-adversarial network was trained on 64 brain tumour patients with paired MR-CT images to generate synthetic CTs (sCT) from combined T1-T2 MRs of three orthogonal planes. A Bayesian neural network predicts Laplacian distributions for all voxels with parameters (µ, b). A robust proton plan was optimized using three sCTs of µ and µ±b. The dosimetric differences between the plan from sCT (sPlan) and the recalculated plan (rPlan) on planning CT (pCT) were quantified for each patient. The uncertainty-aware robust plan was compared to conventional robust (global ± 3 %) and non-robust plans. RESULTS: In 8-fold cross-validation, sCT-pCT image differences (Mean-Absolute-Error) were 80.84 ± 9.84HU (body), 35.78 ± 6.07HU (soft tissues) and 221.88 ± 31.69HU (bones), with Dice scores of 90.33 ± 2.43 %, 95.13 ± 0.80 %, and 85.53 ± 4.16 %, respectively. The uncertainty distribution positively correlated with absolute prediction error (Correlation Coefficient: 0.62 ± 0.01). The uncertainty-conditioned robust optimisation improved the rPlan-sPlan agreement, e.g., D95 absolute difference (CTV) was 1.10 ± 1.24 % compared to conventional (1.64 ± 2.71 %) and non-robust (2.08 ± 2.96 %) optimisation. This trend was consistent across all target and organs-at-risk indexes. CONCLUSION: The enhanced framework incorporates 3D uncertainty prediction and generates high-quality sCTs from MR images. The framework also facilitates conditioned robust optimisation, bolstering proton plan robustness against network prediction errors. The innovative feature of uncertainty visualisation and robust analyses contribute to evaluating sCT clinical utility for individual patients.

Technical note: development of a simulation framework, enabling the investigation of locally tuned single energy proton radiography.

Range uncertainties remain a limitation for the confined dose distribution that proton therapy can offer. The uncertainty stems from the ambiguity when translating CT Hounsfield Units (HU) into proton stopping powers. Proton Radiography (PR) can be used to verify the proton range. Specifically, PR can be used as a quality-control tool for CBCT-based synthetic CTs. An essential part of the work illustrating the potential of PR has been conducted using multi-layer ionization chamber (MLIC) detectors and mono-energetic PR. Due to the dimensions of commercially available MLICs, clinical adoption is cumbersome. Here, we present a simulation framework exploring locally-tuned single energy (LTSE) proton radiography and corresponding potential compact PR detector designs. Based on a planning CT data set, the presented framework models the water equivalent thickness. Subsequently, it analyses the proton energies required to pass through the geometry within a defined ROI. In the final step, an LTSE PR is simulated using the MCsquare Monte Carlo code. In an anatomical head phantom, we illustrate that LTSE PR allows for a significantly shorter longitudinal dimension of MLICs. We compared PR simulations for two exemplary 30 × 30 mm2proton fields passing the phantom at a 90° angle at an anterior and a posterior location in an iso-centric setup. The longitudinal distance over which all spots per field range out is significantly reduced for LTSE PR compared to mono-energetic PR. In addition, we illustrate the difference in shape of integral depth dose (IDD) when using constrained PR energies. Finally, we demonstrate the accordance of simulated and experimentally acquired IDDs for an LTSE PR acquisition. As the next steps, the framework will be used to investigate the sensitivity of LTSE PR to various sources of errors. Furthermore, we will use the framework to systematically explore the dimensions of an optimized MLIC design for daily clinical use.

Technical note: Towards more realistic 4DCT(MRI) numerical lung phantoms.

BACKGROUND: Numerical 4D phantoms, together with associated ground truth motion, offer a flexible and comprehensive data set for realistic simulations in radiotherapy and radiology in target sites affected by respiratory motion. PURPOSE: We present an openly available upgrade to previously reported methods for generating realistic 4DCT lung numerical phantoms, which now incorporate respiratory ribcage motion and improved lung density representation throughout the breathing cycle. METHODS: Density information of reference CTs, toget her with motion from multiple breathing cycle 4DMRIs have been combined to generate synthetic 4DCTs (4DCT(MRI)s). Inter-subject correspondence between the CT and MRI anatomy was first established via deformable image registration (DIR) of binary masks of the lungs and ribcage. Ribcage and lung motions were extracted independently from the 4DMRIs using DIR and applied to the corresponding locations in the CT after post-processing to preserve sliding organ motion. In addition, based on the Jacobian determinant of the resulting deformation vector fields, lung densities were scaled on a voxel-wise basis to more accurately represent changes in local lung density. For validating this process, synthetic 4DCTs, referred to as 4DCT(CT)s, were compared to the originating 4DCTs using motion extracted from the latter, and the dosimetric impact of the new features of ribcage motion and density correction were analyzed using pencil beam scanned proton 4D dose calculations. RESULTS: Lung density scaling led to a reduction of maximum mean lung Hounsfield units (HU) differences from 45 to 12 HU when comparing simulated 4DCT(CT)s to their originating 4DCTs. Comparing 4D dose distributions calculated on the enhanced 4DCT(CT)s to those on the original 4DCTs yielded 2%/2 mm gamma pass rates above 97% with an average improvement of 1.4% compared to previously reported phantoms. CONCLUSIONS: A previously reported 4DCT(MRI) workflow has been successfully improved and the resulting numerical phantoms exhibit more accurate lung density representations and realistic ribcage motion.

Deformable vector fields warping for modelling of irregular breathing.

Purpose 4D computed tomography (4DCT) is the clinical standard to image organ motion in radiotherapy, although it is limited in imaging breathing variability. We propose a method to transfer breathing motion across longitudinal imaging datasets to include intra-patient variability and verify its performance in lung cancer patients. Methods Five repeated control 4DCTs for 6 non-small cell lung cancer patients were combined into multi-breath datasets (m4DCT) by merging stages of deformable image registration to isolate respiratory motion. The displacement of the centre of mass of the primary tumour and its volume changes were evaluated to quantify intra-patient differences. Internal target volumes defined on the m4DCT were compared with those conventionally drawn on the 4DCT. Results Motion analysis suggests no discontinuity at the junction between successive breaths, confirming the method's ability to merge repeated imaging into a continuum. Motion (variability) is primarily in superior-inferior direction and goes from 14.4 mm (8.7 mm) down to 0.1 mm (0.6 mm), respectively for tumours located in the lower lobes or most apical ones. On average, up to 65% and 74% of the tumour volume was subject to expansion or contraction in the inhalation and exhalation phases. These variations lead to an enlargement of the ITV up to 8% of its volume in our dataset. Conclusion 4DCT can be extended to model variable breathing motion by adding synthetic phases from multiple time-resolved images. The inclusion of this improved knowledge of patients' breathing allows better definition of treatment volumes and their margins for radiation therapy. .

The effect of intra- and inter-fractional motion on target coverage and margins in proton therapy for uveal melanoma.

INTRODUCTION: This study aims to assess the effective lateral margin requirements for target coverage in ocular proton therapy (OPT), considering the unique challenges posed by eye motion and hypofractionation. It specifically addresses the previously unaccounted-for uncertainty contribution of intra-fractional motion, in conjunction with setup uncertainties, on dosimetric determination of lateral margin requirements. Method: The methodology integrates dose calculations from the in-house developed treatment planning system OCULARIS with measured intra-fractional motion, patient models from EyePlan and Monte Carlo (MC) sampling of setup uncertainties. The study is conducted on 16 uveal melanoma patients previously treated in the OPTIS2 treatment room at the Paul Scherrer Institute (PSI). Results: The retrospective simulation analysis highlights a significant impact of non-systematic factors on lateral margin requirements in OPT. Simulations indicate that reducing the 2.5 mm clinical lateral margin, represented by a 2.1 mm margin in this work, would have resulted in inadequate target coverage for two patients, revealing a greater impact of non-systematic factors on lateral margin requirements. Conclusions: This work characterizes intra-fractional motion in 16 OPT patients and identifies limitations of clinical margin selection protocols for OPT applications. A novel framework was introduced to assess margin sufficiency for target coverage. The findings suggest that prior research underestimated non-systematic factors and overestimated systematic contributions to lateral margin components. This re-evaluation highlights the critical need to prioritize the management of non-systematic uncertainty contributions in OPT.

Craniospinal irradiation using pencil beam Scanning: The PSI experience.

INTRODUCTION: We present the dosimetric evaluation of craniospinal irradiation (CSI) treatments delivered with protons at Paul Scherrer Institute (PSI), with special focus on local recurrences and late toxicity outcome. METHODS: This study included 71 children, adolescents and young adults (c-AYA), who received or intended to receive (3 patients, pts) CSI using PBS-PT at PSI between 2004 and January 2021. The most frequent primary tumours were: medulloblastoma (42 pts), ependymoma (8 pts) and germ cell tumors (6 pts). The patients were treated prone on Gantry1 (G1; 22 pts) up to 2017, and afterwards supine on Gantry2 (G2; 49 pts). Accuracy of prone vs. supine setup was evaluated. Nine patients received CSI for local failure (LF) after a first course of local fractionated radiation therapy (RT). For 59/71 patients (excluding three patients not receiving PBS-PT CSI and nine preirradiated) CSI plans were compared considering gantry and planning technique. Detailed analysis of the full treatment (CSI and boost series) was performed for 8 patients presenting with LFs (4 of them presented also distal failure) and for selected patients presenting with late toxicity (G2 to G4) or asymptomatic radiation-induced radiological findings. RESULTS: Supine positioning resulted in lower systematic and random errors as compared to prone (0.25 mm and 0.4 mm systematic errors respectively for supine and prone; random errors in PA direction reduced from 1.8 mm for prone to 1.4 mm for supine). CONCLUSIONS: LFs were not correlated with potential dose inaccuracies or lack of robustness and no correlation of toxicities to enhanced LET have been observed.

A unified generation-registration framework for improved MR-based CT synthesis in proton therapy.

BACKGROUND: The use of magnetic resonance (MR) imaging for proton therapy treatment planning is gaining attention as a highly effective method for guidance. At the core of this approach is the generation of computed tomography (CT) images from MR scans. However, the critical issue in this process is accurately aligning the MR and CT images, a task that becomes particularly challenging in frequently moving body areas, such as the head-and-neck. Misalignments in these images can result in blurred synthetic CT (sCT) images, adversely affecting the precision and effectiveness of the treatment planning. PURPOSE: This study introduces a novel network that cohesively unifies image generation and registration processes to enhance the quality and anatomical fidelity of sCTs derived from better-aligned MR images. METHODS: The approach synergizes a generation network (G) with a deformable registration network (R), optimizing them jointly in MR-to-CT synthesis. This goal is achieved by alternately minimizing the discrepancies between the generated/registered CT images and their corresponding reference CT counterparts. The generation network employs a UNet architecture, while the registration network leverages an implicit neural representation (INR) of the displacement vector fields (DVFs). We validated this method on a dataset comprising 60 head-and-neck patients, reserving 12 cases for holdout testing. RESULTS: Compared to the baseline Pix2Pix method with MAE 124.95 ± $\pm$ 30.74 HU, the proposed technique demonstrated 80.98 ± $\pm$ 7.55 HU. The unified translation-registration network produced sharper and more anatomically congruent outputs, showing superior efficacy in converting MR images to sCTs. Additionally, from a dosimetric perspective, the plan recalculated on the resulting sCTs resulted in a remarkably reduced discrepancy to the reference proton plans. CONCLUSIONS: This study conclusively demonstrates that a holistic MR-based CT synthesis approach, integrating both image-to-image translation and deformable registration, significantly improves the precision and quality of sCT generation, particularly for the challenging body area with varied anatomic changes between corresponding MR and CT.