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.

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.

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.

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.

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.

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.

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.

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.

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.

Quantification of deformable image registration uncertainties for dose accumulation on head and neck cancer proton treatments.

PURPOSE: Head and neck cancer (HNC) patients in radiotherapy require adaptive treatment plans due to anatomical changes. Deformable image registration (DIR) is used in adaptive radiotherapy, e.g. for deformable dose accumulation (DDA). However, DIR's ill-posedness necessitates addressing uncertainties, often overlooked in clinical implementations. DIR's further clinical implementation is hindered by missing quantitative commissioning and quality assurance tools. This study evaluates one pathway for more quantitative DDA uncertainties. METHODS: For five HNC patients, each with multiple repeated CTs acquired during treatment, a simultaneous-integrated boost (SIB) plan was optimized. Recalculated doses were warped individually using multiple DIRs from repeated to reference CTs, and voxel-by-voxel dose ranges determined an error-bar for DDA. Followed by evaluating, a previously proposed early-stage DDA uncertainty estimation method tested for lung cancer, which combines geometric DIR uncertainties, dose gradients and their directional dependence, in the context of HNC. RESULTS: Applying multiple DIRs show dose differences, pronounced in high dose gradient regions. The patient with largest anatomical changes (-13.1 % in ROI body volume), exhibited 33 % maximum uncertainty in contralateral parotid, with 54 % of voxels presenting an uncertainty >5 %. Accumulation over multiple CTs partially mitigated uncertainties. The estimation approach predicted 92.6 % of voxels within ±5 % to the reference dose uncertainty across all patients. CONCLUSIONS: DIR variations impact accumulated doses, emphasizing DDA uncertainty quantification's importance for HNC patients. Multiple DIR dose warping aids in quantifying DDA uncertainties. An estimation approach previously described for lung cancer was successfully validated for HNC, for SIB plans, presenting different dose gradients, and for accumulated treatments.

Multi-institutional experimental validation of online adaptive proton therapy workflows.

Objective.To experimentally validate two online adaptive proton therapy (APT) workflows using Gafchromic EBT3 films and optically stimulated luminescent dosimeters (OSLDs) in an anthropomorphic head-and-neck phantom.Approach.A three-field proton plan was optimized on the planning CT of the head-and-neck phantom with 2.0 Gy(RBE) per fraction prescribed to the clinical target volume. Four fractions were simulated by varying the internal anatomy of the phantom. Three distinct methods were delivered: daily APT researched by the Paul Scherrer Institute (DAPTPSI), online adaptation researched by the Massachusetts General Hospital (OAMGH), and a non-adaptive (NA) workflow. All methods were implemented and measured at PSI. DAPTPSIperformed full online replanning based on analytical dose calculation, optimizing to the same objectives as the initial treatment plan. OAMGHperformed Monte-Carlo-based online plan adaptation by only changing the fluences of a subset of proton beamlets, mimicking the planned dose distribution. NA delivered the initial plan with a couch-shift correction based on in-room imaging. For all 12 deliveries, two films and two sets of OSLDs were placed at different locations in the phantom.Main results.Both adaptive methods showed improved dosimetric results compared to NA. For film measurements in the presence of anatomical variations, the [min-max] gamma pass rates (3%/3 mm) between measured and clinically approved doses were [91.5%-96.1%], [94.0%-95.8%], and [67.2%-93.1%] for DAPTPSI, OAMGH, and NA, respectively. The OSLDs confirmed the dose calculations in terms of absolute dosimetry. Between the two adaptive workflows, OAMGHshowed improved target coverage, while DAPTPSIshowed improved normal tissue sparing, particularly relevant for the brainstem.Significance.This is the first multi-institutional study to experimentally validate two different concepts with respect to online APT workflows. It highlights their respective dosimetric advantages, particularly in managing interfractional variations in patient anatomy that cannot be addressed by non-adaptive methods, such as internal anatomy changes.

Feasibility of the J-PET to monitor the range of therapeutic proton beams.

PURPOSE: The aim of this work is to investigate the feasibility of the Jagiellonian Positron Emission Tomography (J-PET) scanner for intra-treatment proton beam range monitoring. METHODS: The Monte Carlo simulation studies with GATE and PET image reconstruction with CASToR were performed in order to compare six J-PET scanner geometries. We simulated proton irradiation of a PMMA phantom with a Single Pencil Beam (SPB) and Spread-Out Bragg Peak (SOBP) of various ranges. The sensitivity and precision of each scanner were calculated, and considering the setup's cost-effectiveness, we indicated potentially optimal geometries for the J-PET scanner prototype dedicated to the proton beam range assessment. RESULTS: The investigations indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for clinical application. We found that the scanner sensitivity is of the order of 10-5 coincidences per primary proton, while the precision of the range assessment for both SPB and SOBP irradiation plans was found below 1 mm. Among the scanners with the same number of detector modules, the best results are found for the triple-layer dual-head geometry. The results indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for the clinical application, CONCLUSIONS:: We performed simulation studies demonstrating that the feasibility of the J-PET detector for PET-based proton beam therapy range monitoring is possible with reasonable sensitivity and precision enabling its pre-clinical tests in the clinical proton therapy environment. Considering the sensitivity, precision and cost-effectiveness, the double-layer cylindrical and triple-layer dual-head J-PET geometry configurations seem promising for future clinical application.

Patient-specific quality assurance for deformable IMRT/IMPT dose accumulation: Proposition and validation of energy conservation based validation criterion.

BACKGROUND: Deformable image registration (DIR)-based dose accumulation (DDA) is regularly used in adaptive radiotherapy research. However, the applicability and reliability of DDA for direct clinical usage are still being debated. One primary concern is the validity of DDA, particularly for scenarios with substantial anatomical changes, for which energy-conservation problems were observed in conceptual studies. PURPOSE: We present and validate an energy-conservation (EC)-based DDA validation workflow and further investigate its usefulness for actual patient data, specifically for lung cancer cases. METHODS: For five non-small cell lung cancer (NSCLC) patients, DDA based on five selective DIR methods were calculated for five different treatment plans, which include one intensity-modulated photon therapy (IMRT), two intensity-modulated proton therapy (IMPT), and two combined proton-photon therapy (CPPT) plans. All plans were optimized on the planning CT (planCT) acquired in deep inspiration breath-hold (DIBH) and were re-optimized on the repeated DIBH CTs of three later fractions. The resulting fractional doses were warped back to the planCT using each DIR. An EC-based validation of the accumulation process was implemented and applied to all DDA results. Correlations between relative organ mass/volume variations and the extent of EC violation were then studied using Bayesian linear regression (BLR). RESULTS: For most OARs, EC violation within 10% is observed. However, for the PTVs and GTVs with substantial regression, severe overestimation of the fractional energy was found regardless of treatment type and applied DIR method. BLR results show that EC violation is linearly correlated to the relative mass variation (R^2 > 0.95) and volume variation (R^2 > 0.60). CONCLUSION: DDA results should be used with caution in regions with high mass/volume variation for intensity-based DIRs. EC-based validation is a useful approach to provide patient-specific quality assurance of the validity of DDA in radiotherapy.

A fast analytical dose calculation approach for MRI-guided proton therapy.

Objective.Magnetic resonance (MR) is an innovative technology for online image guidance in conventional radiotherapy and is also starting to be considered for proton therapy as well. For MR-guided therapy, particularly for online plan adaptations, fast dose calculation is essential. Monte Carlo (MC) simulations, however, which are considered the gold standard for proton dose calculations, are very time-consuming. To address the need for an efficient dose calculation approach for MRI-guided proton therapy, we have developed a fast GPU-based modification of an analytical dose calculation algorithm incorporating beam deflections caused by magnetic fields.Approach.Proton beams (70-229 MeV) in orthogonal magnetic fields (0.5/1.5 T) were simulated using TOPAS-MC and central beam trajectories were extracted to generate look-up tables (LUTs) of incremental rotation angles as a function of water-equivalent depth. Beam trajectories are then reconstructed using these LUTs for the modified ray casting dose calculation. The algorithm was validated against MC in water, different materials and for four example patient cases, whereby it has also been fully incorporated into a treatment plan optimisation regime.Main results.Excellent agreement between analytical and MC dose distributions could be observed with sub-millimetre range deviations and differences in lateral shifts <2 mm even for high densities (1000 HU). 2%/2 mm gamma pass rates were comparable to the 0 T scenario and above 94.5% apart for the lung case. Further, comparable treatment plan quality could be achieved regardless of magnetic field strength.Significance.A new method for accurate and fast proton dose calculation in magnetic fields has been developed and successfully implemented for treatment plan optimisation.

Large anatomical changes in head-and-neck cancers - A dosimetric comparison of online and offline adaptive proton therapy.

Purpose: This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. Methods: IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. Results: Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. Conclusion: Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

Optically stimulated luminescence dosimeters for simultaneous measurement of point dose and dose-weighted LET in an adaptive proton therapy workflow.

Purpose: To demonstrate the suitability of optically stimulated luminescence detectors (OSLDs) for accurate simultaneous measurement of the absolute point dose and dose-weighted linear energy transfer (LETD) in an anthropomorphic phantom for experimental validation of daily adaptive proton therapy. Methods: A clinically realistic intensity-modulated proton therapy (IMPT) treatment plan was created based on a CT of an anthropomorphic head-and-neck phantom made of tissue-equivalent material. The IMPT plan was optimized with three fields to deliver a uniform dose to the target volume covering the OSLDs. Different scenarios representing inter-fractional anatomical changes were created by modifying the phantom. An online adaptive proton therapy workflow was used to recover the daily dose distribution and account for the applied geometry changes. To validate the adaptive workflow, measurements were performed by irradiating Al2O3:C OSLDs inside the phantom. In addition to the measurements, retrospective Monte Carlo simulations were performed to compare the absolute dose and dose-averaged LET (LETD) delivered to the OSLDs. Results: The online adaptive proton therapy workflow was shown to recover significant degradation in dose conformity resulting from large anatomical and positioning deviations from the reference plan. The Monte Carlo simulations were in close agreement with the OSLD measurements, with an average relative error of 1.4% for doses and 3.2% for LETD. The use of OSLDs for LET determination allowed for a correction for the ionization quenched response. Conclusion: The OSLDs appear to be an excellent detector for simultaneously assessing dose and LET distributions in proton irradiation of an anthropomorphic phantom. The OSLDs can be cut to almost any size and shape, making them ideal for in-phantom measurements to probe the radiation quality and dose in a predefined region of interest. Although we have presented the results obtained in the experimental validation of an adaptive proton therapy workflow, the same approach can be generalized and used for a variety of clinical innovations and workflow developments that require accurate assessment of point dose and/or average LET.