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Abstract Ion-beam radiotherapy is an advanced cancer treatment modality offering steep dose gradients and a high biological effectiveness. These gradients make the therapy vulnerable to patient-setup and anatomical changes between treatment fractions, which may go unnoticed. Charged fragments from nuclear interactions of the ion beam with the patient tissue may carry information about the treatment quality. Currently, the fragments escape the patient undetected. Inter-fractional in-vivo treatment monitoring based on these charged nuclear fragments could make ion-beam therapy safer and more efficient. We developed an ion-beam monitoring system based on 28 hybrid silicon pixel detectors (Timepix3) to measure the distribution of fragment origins in three dimensions. The system design choices as well as the ion-beam monitoring performance measurements are presented in this manuscript. A spatial resolution of $${{4}\,\hbox {mm}}$$ 4 mm along the beam axis was achieved for the measurement of individual fragment origins. Beam-range shifts of $${1.5}\,\hbox {mm}$$ 1.5 mm were identified in a clinically realistic treatment scenario with an anthropomorphic head phantom. The monitoring system is currently being used in a prospective clinical trial at the Heidelberg Ion Beam Therapy Centre for head-and-neck as well as central nervous system cancer patients.

Abstract Background Particle therapy makes a noteworthy contribution in the treatment of tumor diseases. In order to be able to irradiate from different angles, usually expensive, complex and large gantries are used. Instead rotating the beam via a gantry, the patient itself might be rotated. Here we present tolerance and compliance of volunteers for a fully-enclosed patient rotation system in a clinical magnetic resonance (MR)-scanner for potential use in MR-guided radiotherapy, conducted within a prospective evaluation study. Methods A patient rotation system was used to simulate and perform magnetic resonance imaging (MRI)-examinations with 50 volunteers without an oncological question. For 20 participants, the MR-examination within the bore was simulated by introducing realistic MRI noise, whereas 30 participants received an examination with image acquisition. Initially, body parameters and claustrophobia were assessed. The subjects were then rotated to different angles for simulation (0°, 45°, 90°, 180°) and imaging (0°, 70°, 90°, 110°). At each angle, anxiety and motion sickness were assessed using a 6-item State-Trait-Anxiety-Inventory (STAI-6) and a modified Motion Sickness Assessment Questionnaire (MSAQ). In addition, general areas of discomfort were evaluated. Results Out of 50 subjects, three (6%) subjects terminated the study prematurely. One subject dropped out during simulation due to nausea while rotating to 45°. During imaging, further two subjects dropped out due to shoulder pain from positioning at 90° and 110°, respectively. The average result for claustrophobia (0 = no claustrophobia to 4 = extreme claustrophobia) was none to light claustrophobia (average score: simulation 0.64 ± 0.33, imaging 0.51 ± 0.39). The mean anxiety scores (0% = no anxiety to 100% = maximal anxiety) were 11.04% (simulation) and 15.82% (imaging). Mean motion sickness scores (0% = no motion sickness to 100% = maximal motion sickness) of 3.5% (simulation) and 6.76% (imaging) were obtained across all participants. Conclusion Our study proves the feasibility of horizontal rotation in a fully-enclosed rotation system within an MR-scanner. Anxiety scores were low and motion sickness was only a minor influence. Both anxiety and motion sickness showed no angular dependency. Further optimizations with regard to immobilization in the rotation device may increase subject comfort.

Proton therapy (PT) is an advancing radiotherapy modality increasingly integrated into clinical settings, transitioning from research facilities to hospital environments. A critical aspect of the commissioning of a proton pencil beam scanning delivery system is the acquisition of experimental beam data for accurate beam modelling within the treatment planning system (TPS). These guidelines describe in detail the acquisition of proton pencil beam modelling data. First, it outlines the intrinsic characteristics of a proton pencil beam—energy distribution, angular-spatial distribution and particle number. Then, it lists the input data typically requested by TPSs. Finally, it describes in detail the set of experimental measurements recommended for the acquisition of proton pencil beam modelling data—integrated depth-dose curves, spot maps in air, and reference dosimetry. The rigorous characterization of these beam parameters is essential for ensuring the safe and precise delivery of proton therapy treatments.

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I. Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1–10.5 Gy (total doses 32.4–42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks. Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression. Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity. Impact and implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials. Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374).

Abstract Background Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC. Methods Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival. Discussion PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques. Trial registration ClinicalTrials.gov: NCT05237453 .

Purpose: Surface-guided radiation therapy (SGRT) has been investigated intensively to ensure correct patient positioning during a radiation therapy course. Although the implementation is well defined for photon-beam facilities, only a few analyses have been published for ion-beam therapy centers. To investigate the accuracy, reliability, and efficiency of SGRT used in ion-beam treatments against the conventional skin marks, a retrospective study of a unique SGRT installation in an ion gantry treatment room was conducted, where the environment is quite different to conventional radiation therapy. Methods and Materials: There were 32 patients, divided into 3 cohorts—pelvis, limb, and chest/spine tumors—and treated with ion-beams. Two patient positioning workflows based on 300 fractions were compared: workflow with skin marks and workflow with SGRT. Position verification was followed by planar kilo voltage imaging. After image matching, 6 degrees of freedom corrections were recorded to assess interfraction positioning errors. In addition, the time required for patient positioning, image matching, and the number of repeated kilo voltage imaging also were gathered. Results: SGRT decreased the translational magnitude shifts significantly (P < .05) by 0.5 ± 1.4 mm for pelvis and 1.9 ± 0.5 mm for limb, whereas for chest/spine, it increased by 0.7 ± 0.3 mm. Rotational corrections were predominantly lowered with SGRT for all cohorts with significant differences in pitch for pelvis (P = .002) and chest/spine (P = .009). The patient positioning time decreased by 18%, 9%, and 15% for pelvis, limb, and chest/spine, respectively, compared with skin marks. By using SGRT, 53% of all studied patients had faster positioning time, and 87.5% had faster matching time. Repositioning and consequent reimaging decreased from about 7% to 2% with a statistically significant difference of .042. Conclusions: The quality of patient positioning before ion-beam treatments has been optimized by using SGRT without additional imaging dose. SGRT clearly reduced inefficiencies in the patient positioning workflow.

The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments.

Fiducial markers are used for image guidance to verify the correct positioning of the target for the case of tumors that can suffer interfractional motion during proton therapy. The markers should be visible on daily imaging, but at the same time, they should produce minimal streak artifacts in the CT scans for treatment planning and induce only slight dose perturbations during particle therapy. In this work, these three criteria were experimentally investigated at the Heidelberg Ion Beam Therapy Center. Several small fiducial markers with different geometries and materials (gold, platinum, and carbon-coated ZrO2) were evaluated. The streak artifacts on treatment planning CT were measured with and without iMAR correction, showing significantly smaller artifacts from markers lighter than 6 mg and a clear improvement with iMAR correction. Daily imaging as X-ray projections and in-room mobile CT were also performed. Markers heavier than 6 mg showed a better contrast in the X-ray projections, whereas on the images from the in-room mobile CT, all markers were clearly visible. In the other part of this work, fluence perturbations of proton beams were measured for the same markers by using a tracker system of several high spatial resolution CMOS pixel sensors. The measurements were performed for single-energy beams, as well as for a spread-out Bragg peak. Three-dimensional fluence distributions were computed after reconstructing all particle trajectories. These measurements clearly showed that the ZrO2 markers and the low-mass gold/platinum markers (0.35mm diameter) induce perturbations being 2–3 times lower than the heavier gold or platinum markers of 0.5mm diameter. Monte Carlo simulations, using the FLUKA code, were used to compute dose distributions and showed good agreement with the experimental data after adjusting the phase space of the simulated proton beam compared to the experimental beam.

Abstract Background The targeting accuracy of proton therapy (PT) for moving soft-tissue tumours is expected to greatly improve by real-time magnetic resonance imaging (MRI) guidance. The integration of MRI and PT at the treatment isocenter would offer the opportunity of combining the unparalleled soft-tissue contrast and real-time imaging capabilities of MRI with the most conformal dose distribution and best dose steering capability provided by modern PT. However, hybrid systems for MR-integrated PT (MRiPT) have not been realized so far due to a number of hitherto open technological challenges. In recent years, various research groups have started addressing these challenges and exploring the technical feasibility and clinical potential of MRiPT. The aim of this contribution is to review the different aspects of MRiPT, to report on the status quo and to identify important future research topics. Methods Four aspects currently under study and their future directions are discussed: modelling and experimental investigations of electromagnetic interactions between the MRI and PT systems, integration of MRiPT workflows in clinical facilities, proton dose calculation algorithms in magnetic fields, and MRI-only based proton treatment planning approaches. Conclusions Although MRiPT is still in its infancy, significant progress on all four aspects has been made, showing promising results that justify further efforts for research and development to be undertaken. First non-clinical research solutions have recently been realized and are being thoroughly characterized. The prospect that first prototype MRiPT systems for clinical use will likely exist within the next 5 to 10 years seems realistic, but requires significant work to be performed by collaborative efforts of research groups and industrial partners.

Background and purpose: Proton therapy may be promising for treating non-small-cell lung cancer due to lower doses to the lung and heart, as compared to photon therapy. A reported challenge is degradation, i.e., a smoothing of the depth-dose distribution due to heterogeneous lung tissue. For pencil beams, this causes a distal falloff widening and a peak-to-plateau ratio decrease, not considered in clinical treatment planning systems. Materials and methods: We present a degradation model implemented into an analytical dose calculation, fully integrated into a treatment planning workflow. Degradation effects were investigated on target dose, distal dose falloffs, and mean lung dose for ten patient cases with varying anatomical characteristics. Results: For patients with pronounced range straggling (in our study large tumors, or lesions close to the mediastinum), degradation effects were restricted to a maximum decrease in target coverage (D95 of the planning target volume) of 1.4%. The median broadening of the distal 80–20% dose falloffs was 0.5 mm at the maximum. For small target volumes deep inside lung tissue, however, the target underdose increased considerably by up to 26%. The mean lung dose was not negatively affected by degradation in any of the investigated cases. Conclusion: For most cases, dose degradation due to heterogeneous lung tissue did not yield critical organ at risk overdosing or overall target underdosing. However, for small and deep-seated tumors which can only be reached by penetrating lung tissue, we have seen substantial local underdose, which deserves further investigation, also considering other prevalent sources of uncertainty.

Particle therapy is a well established clinical treatment of tumors. More than one hundred particle therapy centers are in operation world-wide. The advantage of using hadrons like protons or carbon ions as particles for tumor irradiation is the distinct peak in the depth-dependent energy deposition, which can be exploited to accurately deposit doses in the tumor cells. To guarantee this, high accuracy in monitoring and control of the particle beam is of the utmost importance. Before the particle beam enters the patient, it traverses a monitoring system which has to give fast feedback to the beam control system on position and dose rate of the beam while minimally interacting with the beam. The multi-wire chambers mostly used as beam position monitors have their limitations when a fast response time is required (drift time). Future developments such as MRI-guided ion beam therapy pose additional challenges for the beam monitoring system, such as tolerance of magnetic fields and acoustic noise (vibrations). Solid-state detectors promise to overcome these limitations and the higher resolution they offer can create additional benefits. This article presents the evaluation of an HV-CMOS detector for beam monitoring, provides results from feasibility studies in a therapeutic beam, and summarizes the concepts towards the final large-scale assembly and readout system.

BackgroundTo investigate deviations between planned and applied treatment doses for hypofractionated prostate radiotherapy and to quantify dosimetric accuracy in dependence of the image guidance frequency.MethodsDaily diagnostic in-room CTs were carried out in 10 patients in treatment position as image guidance for hypofractionated prostate radiotherapy. Fraction doses were mapped to the planning CTs and recalculated, and applied doses were accumulated voxel-wise using deformable registration. Non-daily imaging schedules were simulated by deriving position correction vectors from individual scans and used to rigidly register the following scans until the next repositioning before dose recalculation and accumulation. Planned and applied doses were compared regarding dose-volume indices and TCP and NTCP values in dependence of the imaging and repositioning frequency.ResultsDaily image-guided repositioning was associated with only negligible deviations of analyzed dose-volume parameters and conformity/homogeneity indices for the prostate, bladder and rectum. Average CTV T did not significantly deviate from the plan values, and rectum NTCPs were highly comparable, while bladder NTCPs were reduced. For non-daily image-guided repositioning, there were significant deviations in the high-dose range from the planned values. Similarly, CTV dose conformity and homogeneity were reduced. While TCPs and rectal NTCPs did not significantly deteriorate for non-daily repositioning, bladder NTCPs appeared falsely diminished in dependence of the imaging frequency.ConclusionUsing voxel-by-voxel dose accumulation, we showed for the first time that daily image-guided repositioning resulted in only negligible dosimetric deviations for hypofractionated prostate radiotherapy. Regarding dosimetric aberrations for non-daily imaging, daily imaging is required to adequately deliver treatment.

Abstract Background Uncertainties associated with the delivery of treatment to moving organs might compromise the accuracy of treatment. This study explores the impact of intra-fractional anatomical changes in pancreatic patients treated with charged particles delivered using a scanning beam. The aim of this paper is to define the potential source of uncertainties, quantify their effect, and to define clinically feasible strategies to reduce them. Methods The study included 14 patients treated at our facility with charged particles (protons or 12C) using intensity modulated particle therapy (IMPT). Treatment plans were optimized using the Treatment Planning System (TPS) Syngo® RT Planning. The pre-treatment dose distribution under motion (4D) was simulated using the TPS TRiP4D and the dose delivered for some of the treatment fractions was reconstructed. The volume receiving at least 95% of the prescribed dose (V95CTV) and the target dose homogeneity were evaluated. The results from the 4D dose calculations were compared with dose distributions in the static case and its variation correlated with the internal motion amplitude and plan modulation, through the Pearson correlation coefficient, as well the significant p-value. The concept of the modulation index (MI) was introduced to assess the degree of modulation of IMPT plans, through the quantification of intensity gradients between neighboring pencil beams. Results The induced breathing motion together with dynamic beam delivery results in an interplay effect, which affects the homogeneity and target coverage of the dose distribution. This effect is stronger (∆V95CTV > 10%) for patients with tumor motion amplitude above 5 mm and a highly modulated dose distribution between and within fields. The MI combined with the internal motion amplitude is shown to correlate with the target dose degradation and a lack of plan robustness against range and positioning uncertainties. Conclusions Under internal motion the use of inhomogeneous plans results in a decrease in the dose homogeneity and target coverage of dose distributions in comparison to the static case. Plan robustness can be improved by using multiple beams and avoiding beam entrance directions susceptible to density changes. 4D dose calculations support the selection of the most suitable plan for the specific patient’s anatomy.

Abstract Background With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor’s generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the “clinical research group heavy ion therapy” and funded by the German Research Council (DFG, KFO 214). Methods Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months. Results In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7–56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8–45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08–34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2–87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6–55,3). Conclusion Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient.

Abstract Background To evaluate the impact of 68Ga-DOTATOC-PET on treatment planning and sparing of normal tissue in the treatment of skull base meningioma with advanced photons and protons. Methods From the institutional database consisting of 507 skull base meningiomas 10 patients were chosen randomly for the present analysis. Target volume definition was performed based on CT and MRI only, as well as with additional 68Ga-DOTATOC-PET. Treatment plans were performed for Intensity Modulated Radiotherapy (IMRT) and proton therapy using active raster scanning on both target volumes. We calculated doses to relevant organs at risk (OAR), conformity indices as well as differences in normal tissue sparing between both radiation modalities based on CT/MRI planning as well as CT/MRI/PET planning. Results For photon treatment plans, PET-based treatment plans showed a reduction of brain stem Dmax and Dmedian for different levels of total dose. At the optic chiasm, use of 68Ga-DOTATOC significantly reduces Dmax; moreover, the Dmedian is reduced in most cases, too. For both right and left optic nerve, reduction of dose by addition of 68Ga-DOTATOC-PET is minimal and depends on the anatomical location of the meningioma. In protons, the impact of 68Ga-DOTATOC-PET is minimal compared to photons. Conclusion Addition of 68Ga-DOTATOC-PET information into treatment planning for skull base meningiomas has a significant impact on target volumes. In most cases, PET-planning leads to significant reductions of the treatment volumes. Subsequently, reduced doses are applied to OAR. Using protons, the benefit of additional PET is smaller since target coverage is more conformal and dose to OAR is already reduced compared to photons. Therefore, PET-imaging has the greatest margin of benefit in advanced photon techniques, and combination of PET-planning and high-precision treatment leads to comparable treatment plans as with protons.

Abstract Background Meningiomas of the skull base account for 25–30% of all meningiomas. Due to the complex structure of the cranial base and its close proximity to critical structures, surgery is often associated with substantial morbidity. Treatment options include observation, aggressive surgical intervention, stereotactic or conventional radiotherapy. In this analysis we evaluate the outcome of 110 patients with meningiomas of the skull base treated with particle therapy. It was performed within the framework of the “clinical research group heavy ion therapy” and supported by the German Research Council (DFG, KFO 214). Methods Between May 2010 and November 2014, 110 Patients with skull base meningioma were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT). Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4). Sixty meningiomas were benign (WHO °I); whereas 8 were high-risk (WHO °II (n = 7) and °III (n = 1)). In 42 cases histology was not examined, since no surgery was performed. Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at Heidelberg Ion Therapy Center (HIT) using raster-scanning technique for active beam delivery. Fifty one patients (46.4%) received radiotherapy due to tumor progression, 17 (15.5%) after surgical resection and 42 (38.2%) as primary treatment. Results Median follow-up in this analysis was 46,8 months (95% CI 39,9–53,7; Q1-Q3 34,3–61,7). Particle radiotherapy could be performed safely without toxicity-related interruptions. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered excellent overall local control rates with 100% progression-free survival (PFS) after 36 months and 96.6% after 60 months. Median PFS was not reached due to the small number of events. Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6% vs. 75.0%, p = 0,02). Overall survival was 96.2% after 60 months and 92.0% after 72 months from therapy. Of six documented deaths, five were definitely not and the sixth probably not meningioma-related. Conclusion Particle radiotherapy is an excellent treatment option for patients with meningiomas of the skull base and can lead to long-term tumor control with minimal side effects. Other prospective studies with longer follow-up will be necessary to further confirm the role of particle radiotherapy in skull base meningioma.

Abstract Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer.

Abstract Background Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. Methods Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). Results The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. Conclusions Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.

Abstract Background Managing inter-fractional anatomy changes is a challenging task in radiotherapy of pancreatic tumors, especially in scanned carbon-ion delivery. This treatment planning study aims to focus on clinically feasible solutions, such as the beam angle selection and margin design to increase the robustness against inter-fractional uncertainties. Methods This study included 10 patients with weekly 3D-CT imaging and physician-approved Clinical Target Volume (CTV). The study was directed to keep the CTV-coverage using six beam angle configurations in combination with different Internal Target Volume (ITV) concepts. These were: geometric-margin (symmetric 3 and 5 mm margin); range-equivalent margins with an isotropic HU replacement; and to evaluate the need of asymmetric margins the water-equivalent range path (WEPL) was determined per patient from the set of CTs. Plan optimization and forward dose calculation in each week-CT were performed with the research treatment planning system TRiP98 and the plan quality evaluated in terms of CTV coverage (V95CTV) and homogeneity dose (HCTV = D5-D95). Results The beam geometry had a substantial impact on the target irradiation over the treatment course, with the single posterior or two beams showing the best average coverage of the CTV. The use of geometric margins for the more robust beam geometries showed acceptable results, with a V95CTV of (99.2 ± 1.2)% for the 5 mm-margin. For the non-robust configurations, due to substantial changes in the radiological depth, the use of this margin results in a V95CTV that might be below 80%, only showing improvement when the range changes are included. Conclusions Selection of adequate beam configurations and treatment margins in ion-beam therapy of pancreatic tumors is of great importance. For a single posterior beam or two beam configurations, application of geometrical margins compensate for dose degradation induced by inter-fractional anatomy changes for the majority of the analyzed treatment fractions.

Background and purpose: To analyze divergences between the planned and applied treatment doses for post-prostatectomy radiotherapy to the prostatic fossa on a voxel-by-voxel basis based on interfractional anatomic variations and imaging frequency.Materials and methods: For 10 patients receiving intensity-modulated postoperative radiotherapy to the prostatic fossa, position verification was carried out by daily in-room CT imaging in treatment position (340 fraction CTs). Applied fraction doses were recalculated on daily CT scans, and treatment doses were accumulated on a voxel-by-voxel basis after deformable image registration. To simulate weekly imaging, derived weekly position correction vectors were used to rigidly register all daily scans of the respective treatment week onto the planning CT before dose accumulation. Detailed dose statistics of the prescribed and applied treatment doses were compared in relation to the frequency of position verification imaging. Derived NTCP and Pinjury values were calculated for the rectum and bladder.Results: Despite a large variability in the pelvic anatomy, daily CT-based patient repositioning resulted in largely negligible deviations of the analyzed dose-volume, conformity, and uniformity parameters from the planned doses for post-prostatectomy radiotherapy, and only the bladder exhibited significant increases in the accumulated mean and median doses. Derived NTCP for the applied doses to the rectum and bladder and Pinjury values did not significantly deviate from the treatment plan. In contrast, weekly CT-based repositioning resulted in significant decreases of the PTV coverage and dose conformity as well as large deviations of the applied doses to the rectum and bladder from the planned doses. Consecutively, NTCP for the rectum and Pinjury were found falsely reduced for weekly patient repositioning.Conclusions: Our data indicate for the first time in a voxel-by-voxel analysis that daily imaging is required for reliable adaptive delivery of intensity-modulated radiotherapy to the prostatic fossa. This work will help guiding adaptive treatment strategies for post-prostatectomy radiotherapy.

Background and purpose: To analyze deviations of the applied from the planned doses on a voxel-by-voxel basis for definitive prostate cancer radiotherapy depending on anatomic variations and imaging frequency.Materials and methods: Daily in-room CT imaging was performed in treatment position for 10 patients with prostate cancer undergoing intensity-modulated radiotherapy (340 fraction CTs). Applied fraction doses were recalculated on daily images, and voxel-wise dose accumulation was performed using a deformable registration algorithm. For weekly imaging, weekly position correction vectors were derived and used to rigidly register daily scans of that week to the planning CT scan prior to dose accumulation. Applied and prescribed doses were compared in dependence of the imaging frequency, and derived TCP and NTCP values were calculated.Results: Daily CT-based repositioning resulted in non-significant deviations of all analyzed dose-volume, conformity and uniformity parameters to the CTV, bladder and rectum irrespective of anatomic changes. Derived average TCP values were comparable, and NTCP values for the applied doses to the bladder and rectum did not significantly deviate from the planned values. For weekly imaging, the applied D2 to the CTV, rectum and bladder significantly varied from the planned doses, and the CTV conformity index and D98 decreased. While TCP values were comparable, the NTCP for the bladder erroneously appeared reduced for weekly repositioning.Conclusions: Based on daily diagnostic quality CT imaging and voxel-wise dose accumulation, we demonstrated for the first time that daily, but not weekly imaging resulted in only negligible deviations of the applied from the planned doses for prostate intensity-modulated radiotherapy. Therefore, weekly imaging may not be adequately reliable for adaptive treatment delivery techniques for prostate. This work will contribute to devising adaptive re-planning strategies for prostate radiotherapy.

The aim of the thesis is to improve treatment plans of carbon ion irradiation by integrating the tissues' specific [Formula: see text]-values for patients with locally advanced pancreatic cancer (LAPC).Five patients with LAPC were included in this study. By the use of the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) treatment plans with carbon ion beams have been created. Dose calculation was based on [Formula: see text]-values for both organs at risk (OAR) and the tumor. Twenty-five treatment plans and thirty-five forward calculations were created. With reference to the anatomy five field configurations were included. Single Beam Optimization (SBO) and Intensity Modulated Particle Therapy (IMPT) were used for optimization. The plans were analyzed with respect to both dose distributions and individual anatomy. The plans were evaluated using a customized index.With regard to the target, a field setup with one single posterior field achieves the highest score in our index. Field setups made up of three fields achieve good results in OAR sparing. Nevertheless, the field setup with one field is superior in complex topographic conditions. But, allocating an [Formula: see text]-value of 2 Gy to the spinal cord leads to critical high maximum doses in the spinal cord. The evaluation of dose profiles showed significant dose peaks at borders of the [Formula: see text]-gradient, especially in case of a single posterior field.Optimization with specific [Formula: see text]-values allows a more accurate view on dose distribution than previously. A field setup with one single posterior field achieves good results in case of difficult topographic conditions, but leads to high maximum doses to the spinal cord. So, field setups with multiple fields seem to be more adequate in case of LAPC, being surrounded by highly radiosensitive normal tissues.