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Purpose: FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage). Methods and Materials: Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated. Results: The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between –6.1%-point and 2.2%-point for optimized patterns. Conclusions: Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH.

Purpose and objective: Besides a dose-rate threshold of 40–100 Gy/s, the FLASH effect may require a dose > 3.5–7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs). Materials and Methods: Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D95%,PTV = 100%Dpres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2). Results: Compared to ABEF, SBPF resulted in a median increase of EQD2mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V100% EQD2, quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2mean and 1.29, 1.18, 1.28 and 1.15 for V100%,EQD2. Conclusion: A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed.

Objective: The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. Methods: We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1–1-2007 and 31–12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. Results: A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. Conclusion: The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.

Background: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and character-istics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa).Methods: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/-tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were cal-culated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. Results: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imag-ing protocols. Sixteen percent (N = 1268) developed >= 1 SPC. SIRs for pelvis and non-pelvis SPC (all insti-tutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints.Conclusion: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.(c) 2023 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 183 (2023) 1-8 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background and purpose: A potential challenge in single-isocenter multi-lesion lung stereotactic body radiotherapy (SBRT) is that patient positioning is not based on each lesion individually, but on the average position of all lesions. This may lead to larger margins compared to treating with one isocenter per lesion, but increases workflow efficiency. The aim of this study was to investigate whether a single-isocenter technique leads to increased normal lung dose compared to a conventional multiple-isocenters technique. Materials and methods: A cohort of 15 NSCLC patients with two or three lesions previously treated with SBRT was subjected to treatment planning with a multiple-isocenter technique and a single-isocenter technique. For the latter, two margin approaches were evaluated: (1) identical margins for each internal target volume (ITV), assuming an average registration for all lesions in cone-beam CT (CBCT) positioning verification and (2) a smaller margin for the largest lesion, assuming an optimal registration for that lesion. For all 45 treatment plans, mean lung dose (MLD) and lungs-V20Gy were evaluated. The study was performed following RATING guidelines. Results: The MLD was 4.9 ± 1.9 Gy (mean ± SD) for multiple-isocenters and 5.4 ± 2.1 Gy and 5.3 ± 2.2 Gy for single-isocenter approach 1 and 2, respectively. V20Gy was 5.5 ± 3.7%, 5.5 ± 3.2% and 5.4 ± 3.3%. A median [range] increase in MLD of 11.6% [−14.9 – 26.8] was observed when comparing single-isocenter treatment plans to those with multiple isocenters. V20Gy increased by 0.2 [−3.4 – 1.3] percentage points. Conclusion: A single-isocenter SBRT technique for lung patients with multiple targets results in clinically acceptable increases in normal lung dose.

Background: Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients. Methods: We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0. Results: 17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1–100%) in the nominal and 80.9% (range 14.3–99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR. Conclusions: Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC

Additional file 2: Table S2. Results of internal validation of the model building procedure through 1000 bootstrap samples.

Additional file 1: Table S1. Frequency of variable selection in 1000 bootstrap samples.

Purpose: In the treatment of cervical cancer, large anatomical deformations, caused by, e.g., tumor shrinkage, bladder and rectum filling changes, organ sliding, and the presence of the brachytherapy (BT) applicator, prohibit the accumulation of external beam radiotherapy (EBRT) and BT dose distributions. This work proposes a structure-wise registration with vector field integration (SW+VF) to map the largely deformed anatomies between EBRT and BT, paving the way for 3D dose accumulation between EBRT and BT. Methods: T2w-MRIs acquired before EBRT and as a part of the MRI-guided BT procedure for 12 cervical cancer patients, along with the manual delineations of the bladder, cervix-uterus, and rectum-sigmoid, were used for this study. A rigid transformation was used to align the bony anatomy in the MRIs. The proposed SW+VF method starts by automatically segmenting features in the area surrounding the delineated organs. Then, each organ and feature pair is registered independently using a feature-based nonrigid registration algorithm developed in-house. Additionally, a background transformation is calculated to account for areas far from all organs and features. In order to obtain one transformation that can be used for dose accumulation, the organ-based, feature-based, and the background transformations are combined into one vector field using a weighted sum, where the contribution of each transformation can be directly controlled by its extent of influence (scope size). The optimal scope sizes for organ-based and feature-based transformations were found by an exhaustive analysis. The anatomical correctness of the mapping was independently validated by measuring the residual distances after transformation for delineated structures inside the cervix-uterus (inner anatomical correctness), and for anatomical landmarks outside the organs in the surrounding region (outer anatomical correctness). The results of the proposed method were compared with the results of the rigid transformation and nonrigid registration of all structures together (AST). Results: The rigid transformation achieved a good global alignment (mean outer anatomical correctness of 4.3 mm) but failed to align the deformed organs (mean inner anatomical correctness of 22.4 mm). Conversely, the AST registration produced a reasonable alignment for the organs (6.3 mm) but not for the surrounding region (16.9 mm). SW+VF registration achieved the best results for both regions (3.5 and 3.4 mm for the inner and outer anatomical correctness, respectively). All differences were significant (p < 0.02, Wilcoxon rank sum test). Additionally, optimization of the scope sizes determined that the method was robust for a large range of scope size values. Conclusions: The novel SW+VF method improved the mapping of large and complex deformations observed between EBRT and BT for cervical cancer patients. Future studies that quantify the mapping error in terms of dose errors are required to test the clinical applicability of dose accumulation by the SW+VF method. (c) 2015 American Association of Physicists in Medicine.

Purpose: The spatial accuracy of deformable image registration (DIR) is important in the implementation of image guided adaptive radiotherapy techniques for cancer in the pelvic region. Validation of algorithms is best performed on phantoms with fiducial markers undergoing controlled large deformations. Excised porcine bladders, exhibiting similar filling and voiding behavior as human bladders, provide such an environment. The aim of this study was to determine the spatial accuracy of different DIR algorithms on CT images of ex vivo porcine bladders with radiopaque fiducial markers applied to the outer surface, for a range of bladder volumes, using various accuracy metrics. Methods: Five excised porcine bladders with a grid of 30-40 radiopaque fiducial markers attached to the outer wall were suspended inside a water-filled phantom. The bladder was filled with a controlled amount of water with added contrast medium for a range of filling volumes (100-400 ml in steps of 50 ml) using a luer lock syringe, and CT scans were acquired at each filling volume. DIR was performed for each data set, with the 100 ml bladder as the reference image. Six intensity-based algorithms (optical flow or demons-based) implemented in the MATLAB platform DIRART, a b-spline algorithm implemented in the commercial software package VelocityAI, and a structure-based algorithm (Symmetric Thin Plate Spline Robust Point Matching) were validated, using adequate parameter settings according to values previously published. The resulting deformation vector field from each registration was applied to the contoured bladder structures and to the marker coordinates for spatial error calculation. The quality of the algorithms was assessed by comparing the different error metrics across the different algorithms, and by comparing the effect of deformation magnitude (bladder volume difference) per algorithm, using the Independent Samples Kruskal-Wallis test. Results: The authors found good structure accuracy without dependency on bladder volume difference for all but one algorithm, and with the best result for the structure-based algorithm. Spatial accuracy as assessed from marker errors was disappointing for all algorithms, especially for large volume differences, implying that the deformations described by the registration did not represent anatomically correct deformations. The structure-based algorithm performed the best in terms of marker error for the large volume difference (100-400 ml). In general, for the small volume difference (100-150 ml) the algorithms performed relatively similarly. The structure-based algorithm exhibited the best balance in performance between small and large volume differences, and among the intensity-based algorithms, the algorithm implemented in VelocityAI exhibited the best balance. Conclusions: Validation of multiple DIR algorithms on a novel physiological bladder phantom revealed that the structure accuracy was good for most algorithms, but that the spatial accuracy as assessed from markers was low for all algorithms, especially for large deformations. Hence, many of the available algorithms exhibit sufficient accuracy for contour propagation purposes, but possibly not for accurate dose accumulation. (C) 2014 American Association of Physicists in Medicine.

Purpose: Computer tomography (CT) scans are used for designing radiotherapy treatment plans. However, the tumor is often better visible in magnetic resonance (MR) images. For liver stereotactic body radiation therapy (SBRT), the planning CT scan is acquired while abdominal compression is applied to reduce tumor motion induced by breathing. However, diagnostic MR scans are acquired under voluntary breath-hold without the compression device. The resulting large differences in liver shape hinder the alignment of CT and MR image sets, which severely limits the integration of the information provided by these images. The purpose of the current study is to develop and validate a nonrigid registration method to align breath-hold MR images with abdominal-compressed CT images, using vessels that are automatically segmented within the liver. Methods: Contrast-enhanced MR and CT images of seven patients with liver cancer were used for this study. The registration method combines automatic vessel segmentation with an adapted version of thin-plate spline robust point matching. The vessel segmentation uses a multiscale vesselness measure, which allows vessels of various thicknesses to be segmented. The nonrigid registration is point-based, and progressively improves the correspondence and transformation between two point sets. Moreover, Results: Liver deformations in the range of 2.8-10.7 mm were found after rigid registration of the CT and MR scans. Low residual distances for vessel bifurcations (average 1.6, range 1.3-1.9 mm) and additional anatomical landmarks (1.5, 1.1-2.4 mm) were found after nonrigid registration. A large amount of outliers were identified (25%-55%) caused by vessels present in only one of the image sets and false positives in the vesselness measure. The nonrigid registration was capable of handling these Conclusions: An accurate CT/MR vessel-guided nonrigid registration for largely deformed livers was developed, tested, and validated. The method, combining vessel segmentation and point matching, was robust against differences in the segmented vessels. The authors conclude that nonrigid registration is required for accurate alignment of abdominal-compressed and uncompressed liver anatomy. Alignment of breath-hold MR and abdominal-compressed CT images can be used to improve tumor localization for

Purpose: Modern radiotherapy requires assessment of patient anatomical changes. By using unidirectional registration methods, the quantified anatomical changes are asymmetric, i.e., depend on the direction of the registration. Moreover, the registration is challenged by the large and complex organ deformations that can occur in, e. g., cervical cancer patients. The aim of this work was to develop, test, and validate a symmetric feature-based nonrigid registration method that can handle organs with large-scale deformations. Methods: A symmetric version of the unidirectional thin plate spline robust point matching (TPS-RPM) algorithm was developed, implemented, tested, and validated. Tests were performed by using the delineated cervix and uterus and bladder in CT scans of five cervical cancer patients. For each patient, five CT scans with a large variability in organ shape, volume, and deformations were acquired. Both the symmetric and the unidirectional algorithm were employed to calculate the registration geometric accuracy (surface distance and surface coverage errors), the inverse consistency, the residual distances after transforming anatomical landmarks, and the registration time. Additionally, to facilitate the further use of our symmetric method, a large set of input parameters was tested. Results: The developed symmetric algorithm handled successfully the registration of bladders with extreme volume change for which TPS-RPM failed. Compared to the unidirectional algorithm the symmetric algorithm improved, for the registration of organs with large volume change, the inverse consistency by 78% and the surface coverage by 46%. Similarly, for organs with small volume change, the symmetric algorithm improved the inverse consistency by 69% and the surface coverage by 13%. The method allowed for anatomically coherent registration in only 35 s for cervixuterus and 151 s for bladder, while keeping the inverse consistency errors around 1 mm and the surface matching errors below 1 mm. Compared to rigid alignment the symmetric method reduced the residual distances between anatomical landmarks from a range of 5.8 +/- 2-70.1 +/- 20.1 mm to a range of 1.9 +/- 0.2-8.5 +/- 5.2 mm. Conclusions: The developed symmetric method could be employed to perform fast, accurate, consistent, and anatomically coherent registration of organs with large and complex deformations. Therefore, the method is a useful tool that could support further developments in high precision image guided radiotherapy. (C) 2010 American Association of Physicists in Medicine. [DOI: 10.1118/1.3443436]

Technical improvements in planning and dose delivery and in verification of patient positioning have substantially widened the therapeutic window for radiation treatment of cancer. However, changes in patient anatomy during the treatment limit the exploitation of these new techniques. To further improve radiation treatments, anatomical changes need to be modeled and accounted for. Nonrigid registration can be used for this purpose. This article describes the design, the implementation, and the validation of a new framework for nonrigid registration for radiotherapy applications. The core of this framework is an improved version of the thin plate spline robust point matching (TPS-RPM) algorithm. The TPS-RPM algorithm estimates a global correspondence and a transformation between the points that represent organs of interest belonging to two image sets. However, the algorithm does not allow for the inclusion of prior knowledge on the correspondence of subset of points, and therefore, it can lead to inconsistent anatomical solutions. In this article TPS-RPM was improved by employing a novel correspondence filter that supports simultaneous registration of multiple structures. The improved method allows for coherent organ registration and for the inclusion of user-defined landmarks, lines, and surfaces inside and outside of structures of interest. A procedure to generate control points from segmented organs is described. The framework parameters r and lambda, which control the number of points and the nonrigidness of the transformation, respectively, were optimized for three sites with different degrees of deformation (head and neck, prostate, and cervix) using two cases per site. For the head and neck cases, the salivary glands were manually contoured on CT scans, for the prostate cases the prostate and the vesicles, and for the cervix cases the cervix uterus, the bladder, and the rectum. The transformation error obtained using the best set of parameters was below 1 mm for all the studied cases. The lengths of the deformation vectors were on average (+/- 1 standard deviation) 5.8 +/- 2.5 and 2.6 +/- 1.1 mm for the head and neck cases, 7.2 +/- 4.5 and 8.6 +/- 1.9 mm for the prostate cases, and 19.0 +/- 11.6 and 14.5 +/- 9.3 mm for the cervix cases. Distinguishable anatomical features were identified for each case and were used to validate the registration by calculating residual distances after transformation: 1.5 +/- 0.8, 2.3 +/- 1.0, and 6.3 +/- 2.9 mm for the head and neck, prostate, and cervix sites, respectively. Finally, the authors demonstrated how the inclusion of these anatomical features in the registration process reduced the residual distances to 0.8 +/- 0.5, 0.6 +/- 0.5, and 1.3 +/- 0.7 mm for the head and neck, prostate, and cervix sites, respectively. The inclusion of additional anatomical features produced more anatomically coherent transformations without compromising the transformation error. The authors concluded that the presented nonrigid registration framework is a powerful tool to simultaneously register multiple segmented organs with very different complexities.

Treatment planning for high precision radiotherapy of head and neck (H&N) cancer patients requires accurate delineation of many structures and lymph node regions. Manual contouring is tedious and suffers from large inter- mid intra-rater variability. To reduce manual labor, we have developed a fully automated, a fully automated, based method for H&N CT image segmentation that employs a novel hierarchical atlas registration approach. This registration strategy makes use of object shape information in the atlas to help improve the registration efficiency mid robustness while, still being able to account for large inter-subject shape differences. Validation results showed that our method provides accurate segmentation for many structure's despite difficulties presented by real clinical data. Comparison of two different, atlas selection strategies is also reported.

In this thesis we have explored different methods to manage abdominal organ motion occurring while treating pancreatic cancer patients with stereotactic body radiotherapy. Organ motion management can contribute to reduce healthy organs radiation exposure, and hence, can aid to improve further the clinical outcomes of this challenging treatment site.

Intensity modulated proton therapy (IMPT) in head and neck squamous cell carcinoma (HNSCC) offers superior advantages over conventional photon therapy, by generating high conformal doses to the target volume and improved sparing of the organ at risks (OARs). Besides, robust treatment planning approaches, which account for uncertainties directly into the plan optimization process, are able to generate high quality plans robust against uncertainties compared to a PTV margin expansion approach. During radiation treatment, patients are prone to present anatomical variations during the treatment course, which can be random deviations in patient positioning, as well as treatment-induced tumor shrinkage and patient weight variations. For IMPT plans using a PTV margin expansion, these anatomical variations might disturb the calculated nominal plan, with a decrease to the dose delivered to the target volume and/or increased dose to the OARs above its tolerance, and a plan adaptation might be needed. However, the influence of these anatomical variations in robustly optimized plans for HNSCC entities has not been determined. The first part of this thesis compared two proton therapy methods, single-field optimization (SFO) and multi-field optimization (MFO), applied to the treatment of unilateral HNSCC target volumes, consisting of a cohort of 8 patients. For each method, a PTV-based and a robustly optimized plan were generated, resulting in four plans per patient. The four plans showed adequate target coverage on the nominal plan, with larger doses to the ipsilateral parotid gland for both SFO approaches. No plan showed a clear advantage when variations in the anatomy during the treatment course were considered, and the same was observe considering additional setup and range uncertainties. Hence, no plan showed a decisive superiority regarding plan robustness and potential need of replanning. In the second part of this thesis, an anatomical robustly optimized plan approach was proposed (aRO), which considers additional CT datasets in the plan optimization, representing random non-rigid patient positioning variations. The aRO approach was compared to a classical robustly optimized plan (cRO) and a PTV-based approach for a cohort of 20 bilateral HNSCC patients. PTV-based and cRO approaches were not sufficient to account for weekly anatomical variations, showing a degradation in the target coverage in 10 and 5 of 20 cases, respectively. Conversely, the proposed aRO approach was able to preserve the target coverage in 19 of 20 cases, with only one patient requiring plan adaptation. An extended robustness analysis conducted on both cRO and aRO plan approaches considering weekly anatomical variations, setup and range errors, showed that the variations in anatomy were the most critical variable for loss in target coverage, while setup and range uncertainties played a minor role. The price of the increased plan robustness for the aRO approach was a significant larger integral dose to the healthy tissue, compared to the cRO plan. However, the increase in integral dose was not reflected on the planned dose to the OARs, which were comparable between both plans. Therefore, the price for a superior plan robustness can be considered as low. In the current clinical practice, the implementation of the aRO approach would be able to reduce the need of plan adaptation. For its application, the acquisition of additional planning CT datasets, considering a complete patient repositioning between scans is required, in order to simulate random non-rigid position variations as simulated in this study by the use of the first two weekly cCTs in the plan optimization. Further studies using multiple planning CT acquisition, including strategies to reduce the patient CT dose such as dual-energy CT and iterative reconstruction algorithms, are needed to confirm the presented findings. Additionally, the aRO approach applied to other body sites and entities might also be investigated. In near future, further in-room imaging methods such as cone-beam CT and magnetic resonance imaging, optimized for proton therapy, might be used to acquire additional datasets. Moreover, alternative approaches capable of modeling variations in patient positioning as biomechanical models and deep learning methods might be able to generate in silico additional image datasets for use in proton treatment planning. In summary, this thesis proposes an additional contribution for robust treatment planning in IMPT, with the generation of treatment plans robust against anatomy variations, together with setup and range uncertainties, which can benefit the clinical workflow by reducing the need of plan adaptation.:Contents List of Figures List of Tables List of Abbreviations 1 Introduction 2 Proton Therapy 2.1 Rationale for Proton Therapy 2.2 Beam Delivery Techniques 2.2.1 Passive Scattering 2.2.2 Pencil Beam Scanning 2.3 Uncertainties in Proton Therapy 2.3.1 Target Volume Definition 2.3.2 Range Uncertainty 2.3.3 Setup Uncertainty 2.3.4 Biological Uncertainty 2.3.5 Anatomical Variations 3 Robust Treatment Planning and Robustness Evaluation 3.1 Robust Treatment Planning 3.1.1 Including Uncertainties in the Optimization 3.1.2 Differences Between Approaches 3.2 Robustness Evaluation 3.2.1 Error Scenarios 3.2.2 Visual Evaluation of Plan Robustness 3.2.3 Summary 4 Illustration of Robust Treatment Planning in a Simple Geometry 4.1 Plan Design 4.2 Plan Results 4.2.1 Doses on Nominal Plan 4.2.2 Influence of Uncertainties in Plan Robustness 4.3 Discussion and Conclusion 5 Evaluation of Robust Treatment Plans in Unilateral Head and Neck Squamous Cell Carcinoma 5.1 Study Design 5.1.1 Calculation Parameters 5.1.2 Plan Robustness Evaluation 5.2 Results 5.2.1 Evaluation of Nominal Plan Doses 5.2.2 Evaluation of Plan Robustness Against Uncertainties 5.3 Discussion 5.4 Conclusions 6 Assessment of Anatomical Robustly Optimized Plans in Bilateral Head and Neck Squamous Cell Carcinoma 6.1 Anatomical Robust Optimization 6.2 Study Design 6.2.1 Calculation Parameters 6.2.2 Assessment of Plan Robustness 6.3 Results 6.3.1 Evaluation of Nominal Plan Doses 6.3.2 Evaluation of Plan Robustness Against Uncertainties 6.4 Discussion 6.4.1 Robustness Against Anatomical Variations 6.4.2 Robustness Against Additional Setup and Range Uncertainties 6.4.3 Study Limitations 6.5 Conclusions 7 Summary 8 Zusammenfassung Bibliography Appendix