Publications by authors named "Damien C Weber"

174 Publications

Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

Radiother Oncol 2022 May 2;172:32-41. Epub 2022 May 2.

Department of Medical Physics, Aarhus University Hospital, Denmark; Dept. of Clinical Medicine, Faculty of Health Sciences, Aarhus University, Denmark.

Purpose: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer.

Materials And Methods: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes.

Results: All PT and XT plans complied with V95% >99% for the nominal plan and V95% >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95% in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95% was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95% was >85%.

Conclusion: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.
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http://dx.doi.org/10.1016/j.radonc.2022.04.029DOI Listing
May 2022

Influence of Radiation Dose, Photon Energy, and Reconstruction Kernel on rho/z Analysis in Spectral Computer Tomography: A Phantom Study.

In Vivo 2022 Mar-Apr;36(2):678-686

Department of Radiology, Kantonsspital Baden, Baden, Switzerland;

Background/aim: The effective atomic number (Z) and electron density relative to water (ρ or Rho) of elements can be derived in dual-energy computed tomography (DECT). The aim of this phantom study was to investigate the effect of different photon energies, radiation doses, and reconstruction kernels on Z and Rho measured in DECT.

Materials And Methods: An anthropomorphic head phantom including five probes of known composition was scanned under three tube-voltage combinations in DECT: Sn140/100 kV, 140/80 kV and Sn140/80 kV with incremented radiation doses. Raw data were reconstructed with four reconstruction kernels (I30, I40, I50, and I70). Rho and Z were measured for each probe for all possible combinations of scan and reconstruction parameters.

Results: DECT-based Rho and Z closely approached the reference values with a mean and maximum error of 1.7% and 6.8%, respectively. Rho was lower for 140/80 kV compared with Sn140/100 kV and Sn140/80 kV with differences being 0.009. Z differed among all tube voltages with the most prominent difference being 0.28 between 140/80 kV and Sn140/100 kV. Z was lower in I70 compared with those of I30 and I40 with a difference of 0.07. Varying radiation dose yielded a variation of 0.0002 in Rho and 0.03 in Z, both considered negligible in practice.

Conclusion: DECT comprises a feasible method for the extraction of material-specific information. Slight variations should be taken into account when different radiation doses, photon energies, and kernels are applied; however, they are considered small and in practice not crucial for an effective tissue differentiation.
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http://dx.doi.org/10.21873/invivo.12753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931898PMC
March 2022

Synthetic 4DCT(MRI) lung phantom generation for 4D radiotherapy and image guidance investigations.

Med Phys 2022 May 17;49(5):2890-2903. Epub 2022 Mar 17.

Center for Proton Therapy, Paul Scherrer Institute, Villigen PSI, Switzerland.

Purpose: Respiratory motion is one of the major challenges in radiotherapy. In this work, a comprehensive and clinically plausible set of 4D numerical phantoms, together with their corresponding "ground truths," have been developed and validated for 4D radiotherapy applications.

Methods: The phantoms are based on CTs providing density information and motion from multi-breathing-cycle 4D Magnetic Resonance imagings (MRIs). Deformable image registration (DIR) has been utilized to extract motion fields from 4DMRIs and to establish inter-subject correspondence by registering binary lung masks between Computer Tomography (CT) and MRI. The established correspondence is then used to warp the CT according to the 4DMRI motion. The resulting synthetic 4DCTs are called 4DCT(MRI)s. Validation of the 4DCT(MRI) workflow was conducted by directly comparing conventional 4DCTs to derived synthetic 4D images using the motion of the 4DCTs themselves (referred to as 4DCT(CT)s). Digitally reconstructed radiographs (DRRs) as well as 4D pencil beam scanned (PBS) proton dose calculations were used for validation.

Results: Based on the CT image appearance of 13 lung cancer patients and deformable motion of five volunteer 4DMRIs, synthetic 4DCT(MRI)s with a total of 871 different breathing cycles have been generated. The 4DCT(MRI)s exhibit an average superior-inferior tumor motion amplitude of 7 ± 5 mm (min: 0.5 mm, max: 22.7 mm). The relative change of the DRR image intensities of the conventional 4DCTs and the corresponding synthetic 4DCT(CT)s inside the body is smaller than 5% for at least 81% of the pixels for all studied cases. Comparison of 4D dose distributions calculated on 4DCTs and the synthetic 4DCT(CT)s using the same motion achieved similar dose distributions with an average 2%/2 mm gamma pass rate of 90.8% (min: 77.8%, max: 97.2%).

Conclusion: We developed a series of numerical 4D lung phantoms based on real imaging and motion data, which give realistic representations of both anatomy and motion scenarios and the accessible "ground truth" deformation vector fields of each 4DCT(MRI). The open-source code and motion data allow foreseen users to generate further 4D data by themselves. These numeric 4D phantoms can be used for the development of new 4D treatment strategies, 4D dose calculations, DIR algorithm validations, as well as simulations of motion mitigation and different online image guidance techniques for both proton and photon radiation therapy.
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http://dx.doi.org/10.1002/mp.15591DOI Listing
May 2022

NTCP Modeling for High-Grade Temporal Radionecroses in a Large Cohort of Patients Receiving Pencil Beam Scanning Proton Therapy for Skull Base and Head and Neck Tumors.

Int J Radiat Oncol Biol Phys 2022 Jun 4;113(2):448-455. Epub 2022 Feb 4.

Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland; University Hospital Zürich, Zürich, Switzerland; University Hospital of Bern (Inselspital), University of Bern, Bern, Switzerland. Electronic address:

Purpose: To develop a normal tissue complication probability model including clinical and dosimetric parameters for high-grade temporal lobe radionecroses (TRN) after pencil beam scanning proton therapy.

Methods And Materials: We included data on 299 patients with skull base and head and neck tumors treated with pencil-beam scan proton therapy, with a total dose of ≥60 Gy (relative biological effectiveness) from May 2004 to November 2018. We considered 9 clinical and 27 dosimetric parameters for the structure-wise modeling of high-grade (grade ≥2) TRN. After eliminating strongly cross-correlated variables, we generated logistic regression models using least absolute shrinkage and selection operator regression. We performed bootstrapping to assess parameter selection robustness and evaluated model performance via cross-correlation by assessing the area under the curve of receiver operating characteristic curves and calibration with a Hosmer-Lemeshow test statistic.

Results: After a median radiologic follow-up of 51.5 months (range, 4-190), 27 patients (9%) developed grade ≥2 TRN. Eleven patients had bitemporal necrosis, resulting in 38 events in 598 temporal lobes for structure-wise analysis. During our bootstrapping analysis, we found that the highest selection frequency was for prescription dose, followed by age, V (%), hypertension, and dose to at least 1 cc (D) (Gy) in the temporal lobe. During our cross-validation, we found that age*prescription-dose*D (Gy)*hypertension was superior in all described test statistics. We built full cohort structure-wise and patient-wise models with maximum area under the curve of receiver operating characteristic curves of 0.79 (structure-wise) and 0.76 (patient-wise).

Conclusions: While developing a logistic regression normal tissue complication probability model to predict grade ≥2 TRN, the best fit was found for the model containing age, prescription dose, D (Gy), and hypertensive blood pressure as risk factors. External validation will be the next step to improve generalizability and potential introduction into clinical routine.
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http://dx.doi.org/10.1016/j.ijrobp.2022.01.047DOI Listing
June 2022

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation.

Radiother Oncol 2022 03 29;168:241-249. Epub 2022 Jan 29.

KU Leuven, University of Leuven, Department of Oncology, Laboratory of Experimental Radiotherapy, Belgium; University Hospitals Leuven, Department of Radiation Oncology, Belgium; Particle Therapy Interuniversitary Center Leuven (PartICLe), Belgium; Leuven Kanker Instituut (LKI), UZ Leuven Gasthuisberg, Belgium.

Purpose: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy.

Methods: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points.

Results: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined.

Conclusion: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org.
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http://dx.doi.org/10.1016/j.radonc.2022.01.018DOI Listing
March 2022

A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy.

Med Phys 2022 Mar 27;49(3):2026-2038. Epub 2022 Jan 27.

Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.

Purpose: In ultrahigh dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumor control. Although many studies show promising results, the underlying biological mechanisms and the relevant delivery parameters are still largely unknown. It is unclear, particularly for scanned proton therapy, how treatment plans could be optimized to maximally exploit this protective FLASH effect.

Materials And Methods: To investigate the potential of pencil beam scanned proton therapy for FLASH treatments, we present a phenomenological model, which is purely based on experimentally observed phenomena such as potential dose rate and dose thresholds, and which estimates the biologically effective dose during FLASH radiotherapy based on several parameters. We applied this model to a wide variety of patient geometries and proton treatment planning scenarios, including transmission and Bragg peak plans as well as single- and multifield plans. Moreover, we performed a sensitivity analysis to estimate the importance of each model parameter.

Results: Our results showed an increased plan-specific FLASH effect for transmission compared with Bragg peak plans (19.7% vs. 4.0%) and for single-field compared with multifield plans (14.7% vs. 3.7%), typically at the cost of increased integral dose compared to the clinical reference plan. Similar FLASH magnitudes were found across the different treatment sites, whereas the clinical benefits with respect to the clinical reference plan varied strongly. The sensitivity analysis revealed that the threshold dose as well as the dose per fraction strongly impacted the FLASH effect, whereas the persistence time only marginally affected FLASH. An intermediate dependence of the FLASH effect on the dose rate threshold was found.

Conclusions: Our model provided a quantitative measure of the FLASH effect for various delivery and patient scenarios, supporting previous assumptions about potentially promising planning approaches for FLASH proton therapy. Positive clinical benefits compared to clinical plans were achieved using hypofractionated, single-field transmission plans. The dose threshold was found to be an important factor, which may require more investigation.
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http://dx.doi.org/10.1002/mp.15459DOI Listing
March 2022

Current practice in proton therapy delivery in adult cancer patients across Europe.

Radiother Oncol 2022 02 11;167:7-13. Epub 2021 Dec 11.

University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, The Netherlands.

Background And Purpose: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres.

Materials And Methods: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT.

Results: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%).

Conclusion: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT.
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http://dx.doi.org/10.1016/j.radonc.2021.12.004DOI Listing
February 2022

A Prospective Study on Health-Related Quality of Life and Patient-Reported Outcomes in Adult Brain Tumor Patients Treated with Pencil Beam Scanning Proton Therapy.

Cancers (Basel) 2021 Sep 29;13(19). Epub 2021 Sep 29.

Center for Proton Therapy, Paul Scherrer Institute, Forschungstrasse 111, 5232 Villigen, Switzerland.

Proton therapy (PT) is delivered to complex brain tumors to obtain an optimal curative treatment with limited toxicity. Value-based oncological medicine is increasingly important, particularly when long-term survival is to be expected. This study aims to evaluate health-related quality of life (HRQOL) and patient reported outcomes (PROs) in patients treated with PT for brain tumors. Adult patients with brain tumors treated with PT filled out the EORTC-QLQ-C30 and BN20 questionnaires up to three years following PT. Toxicity was scored using the CTCAE v4.03. QoL and PRO were correlated to clinical factors. Three-year overall survival, distant brain control and local control rates were 98%, 97% and 84%, respectively. No ≥G3 acute toxicity was observed. Late PT-related ≥G3 severe toxicity occurred in seven patients (5.7%). Lower global QoL scores after PT were significantly correlated to low Karnofsky performance status (KPS) before PT ( = 0.001), surgical complications before PT ( = 0.04) and progressive disease ( = 0.017). A low QLQ-30 summary score at one year follow-up was correlated to sex ( = 0.015), low KPS before PT ( < 0.001), and central nervous system symptoms before PT ( = 0.018). Reported QLQ-BN20 neurological symptoms were correlated to lower KPS at baseline ( < 0.001) and surgical complications before PT ( = 0.03). PT-related toxicity only influenced reported symptoms directly following PT, but not QoL. Although global QoL temporarily decreased after treatment, it improved again from one year onwards. Global QoL and reported symptoms over time were not correlated with the proton therapy and were more related to preexisting symptoms and progressive disease. This study assists in improving patient support in patients with brain tumors receiving PT.
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http://dx.doi.org/10.3390/cancers13194892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507714PMC
September 2021

Types of deviation and review criteria in pretreatment central quality control of tumor bed boost in medulloblastoma-an analysis of the German Radiotherapy Quality Control Panel in the SIOP PNET5 MB trial.

Strahlenther Onkol 2022 Mar 5;198(3):282-290. Epub 2021 Aug 5.

Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstr. 9a, 04103, Leipzig, Germany.

Purpose: In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost.

Patients And Methods: A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly.

Results: Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity.

Conclusion: In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.
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http://dx.doi.org/10.1007/s00066-021-01822-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863746PMC
March 2022

EANO guideline on the diagnosis and management of meningiomas.

Neuro Oncol 2021 11;23(11):1821-1834

Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.
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http://dx.doi.org/10.1093/neuonc/noab150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563316PMC
November 2021

Update of the EPTN atlas for CT- and MR-based contouring in Neuro-Oncology.

Radiother Oncol 2021 07 18;160:259-265. Epub 2021 May 18.

Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf Dresden, Germany; German Cancer Consortium (DKTK), partnersite Dresden and German Cancer Research Center (DKFZ), Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresde, Germany; Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR)., Germany.

Background And Purpose: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs.

Materials And Methods: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature.

Results: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online.

Conclusion: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org.
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http://dx.doi.org/10.1016/j.radonc.2021.05.013DOI Listing
July 2021

Enhanced Deep-Inspiration Breath Hold Superior to High-Frequency Percussive Ventilation for Respiratory Motion Mitigation: A Physiology-Driven, MRI-Guided Assessment Toward Optimized Lung Cancer Treatment With Proton Therapy.

Front Oncol 2021 29;11:621350. Epub 2021 Apr 29.

Exercise Physiology Lab, Department of Health Sciences and Technology, Institute of Human Movement Sciences and Sport, ETH Zurich, Zurich, Switzerland.

To safely treat lung tumors using particle radiation therapy (PRT), motion-mitigation strategies are of critical importance to ensure precise irradiation. Therefore, we compared applicability, effectiveness, reproducibility, and subjects' acceptance of enhanced deep-inspiration breath hold (eDIBH) with high-frequency percussive ventilation (HFPV) by MRI assessment within 1 month. Twenty-one healthy subjects (12 males/9 females; age: 49.5 ± 5.8 years; BMI: 24.7 ± 3.3 kg/m) performed two 1.5 T MRI scans in four visits at weekly intervals under eDIBH and HFPV conditions, accompanied by daily, home-based breath-hold training and spirometric assessments over a 3-week period. eDIBH consisted of 8-min 100% O breathing (3 min resting ventilation, 5 min controlled hyperventilation) prior to breath hold. HFPV was set at 200-250 pulses min and 0.8-1.2 bar. Subjects' acceptance and preference were evaluated by questionnaire. To quantify inter- and intrafractional changes, a lung distance metric representing lung topography was computed for 10 reference points: a motion-invariant spinal cord and nine lung structure contours (LSCs: apex, carina, diaphragm, and six vessels as tumor surrogates distributed equally across the lung). To parameterize individual LSC localizability, measures of their spatial variabilities were introduced and lung volumes calculated by automated MRI analysis. eDIBH increased breath-hold duration by > 100% up to 173 ± 73 s at visit 1, and to 217 ± 67 s after 3 weeks of home-based training at visit 4 ( < 0.001). Measures of vital capacity and lung volume remained constant over the 3-week period. Two vessels in the lower lung segment and the diaphragm yielded a two- to threefold improved positional stability with eDIBH, whereby absolute distance variability was significantly smaller for five LSCs; ≥70% of subjects showed significantly better intrafractional lung motion mitigation under reproducible conditions with eDIBH compared with HFPV with smaller ranges most apparent in the anterior-posterior and cranial-caudal directions. Approximately 80% of subjects preferred eDIBH over HFPV, with "less discomfort" named as most frequent reason. Both, eDIBH, and HFPV were well-tolerated. eDIBH duration was long enough to allow for potential PRT. Variability in lung volume was smaller and position of lung structures more precise with eDIBH. Subjects preferred eDIBH over HFPV. Thus, eDIBH is a very promising tool for lung tumor therapy with PRT, and further investigation of its applicability in patients is warranted.
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http://dx.doi.org/10.3389/fonc.2021.621350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116693PMC
April 2021

Commissioning of a clinical pencil beam scanning proton therapy unit for ultra-high dose rates (FLASH).

Med Phys 2021 Jul 25;48(7):4017-4026. Epub 2021 May 25.

Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.

Purpose: The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultra-high dose rates.

Methods: PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning).

Results: We achieved a transmission of 86% from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5 × 5 mm were achieved for single-spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16 × 1.2 cm . With the use of a nozzle-mounted range shifter, we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with precision within less than 1%.

Conclusions: We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in single-spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research.
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http://dx.doi.org/10.1002/mp.14933DOI Listing
July 2021

An approach for estimating dosimetric uncertainties in deformable dose accumulation in pencil beam scanning proton therapy for lung cancer.

Phys Med Biol 2021 05 10;66(10). Epub 2021 May 10.

Paul Scherrer Institute, Center for Proton Therapy, Switzerland.

Deformable image registration (DIR) is an important component for dose accumulation and associated clinical outcome evaluation in radiotherapy. However, the resulting deformation vector field (DVF) is subject to unavoidable discrepancies when different algorithms are applied, leading to dosimetric uncertainties of the accumulated dose. We propose here an approach for proton therapy to estimate dosimetric uncertainties as a consequence of modeled or estimated DVF uncertainties. A patient-specific DVF uncertainty model was built on the first treatment fraction, by correlating the magnitude differences of five DIR results at each voxel to the magnitude of any single reference DIR. In the following fractions, only the reference DIR needs to be applied, and DVF geometric uncertainties were estimated by this model. The associated dosimetric uncertainties were then derived by considering the estimated geometric DVF uncertainty, the dose gradient of fractional recalculated dose distribution and the direction factor from the applied reference DIR of this fraction. This estimated dose uncertainty was respectively compared to the reference dose uncertainty when different DIRs were applied individually for each dose warping. This approach was validated on seven NSCLC patients, each with nine repeated CTs. The proposed model-based method is able to achieve dose uncertainty distribution on a conservative voxel-to-voxel comparison within ±5% of the prescribed dose to the 'reference' dosimetric uncertainty, for 77% of the voxels in the body and 66%-98% of voxels in investigated structures. We propose a method to estimate DIR induced uncertainties in dose accumulation for proton therapy of lung tumor treatments.
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http://dx.doi.org/10.1088/1361-6560/abf8f5DOI Listing
May 2021

Combining rescanning and gating for a time-efficient treatment of mobile tumors using pencil beam scanning proton therapy.

Radiother Oncol 2021 07 9;160:82-89. Epub 2021 Apr 9.

Center for Proton Therapy, Paul Scherrer Institute (PSI), Villigen PSI, Switzerland. Electronic address:

Background And Purpose: Respiratory motion during proton therapy can severely degrade dose distributions, particularly due to interplay effects when using pencil beam scanning. Combined rescanning and gating treatments for moving tumors mitigates dose degradation, but at the cost of increased treatment delivery time. The objective of this study was to identify the time efficiency of these dose degradation-motion mitigation strategies for different range of motions.

Materials And Methods: Seventeen patients with thoracic or abdominal tumors were studied. Tumor motion amplitudes ranged from 2-30 mm. Deliveries using different combinations of rescanning and gating were simulated with a dense dose spot grid (4 × 4 × 2.5 mm) for all patients and a sparse dose spot grid (8 × 8 × 5 mm) for six patients with larger tumor movements (>8 mm). The resulting plans were evaluated in terms of CTV coverage and time efficiency.

Results: Based on the studied patient cohort, it has been shown that for amplitudes up to 5 mm, no motion mitigation is required with a dense spot grid. For amplitudes between 5 and 10 mm, volumetric rescanning should be applied while maintaining a 100% duty cycle when using a dense spot grid. Although gating could be envisaged to reduce the target volume for intermediate motion, it has been shown that the dose to normal tissues would only be reduced marginally. Moreover, the treatment time would increase. Finally, for larger motion amplitudes, both volumetric rescanning and respiratory gating should be applied with both spot grids. In addition, it has been shown that a dense spot grid delivers better CTV dose coverage than a sparse dose grid.

Conclusion: Volumetric rescanning and/or respiratory gating can be used in order to effectively and efficiently mitigate dose degradation due to tumor movement.
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http://dx.doi.org/10.1016/j.radonc.2021.03.041DOI Listing
July 2021

Effects of deep inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes.

Sci Rep 2021 03 16;11(1):6085. Epub 2021 Mar 16.

Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Radiotherapiepark, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments.
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http://dx.doi.org/10.1038/s41598-021-85401-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966795PMC
March 2021

Proton Therapy for Intracranial Meningioma for the Treatment of Primary/Recurrent Disease Including Re-Irradiation.

Front Oncol 2020 14;10:558845. Epub 2020 Dec 14.

Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.

Meningeal tumors represent approximately 10-25% of primary brain tumors and occur usually in elderly female patients. Most meningiomas are benign (80-85%) and for symptomatic and/or large tumors, surgery, with or without radiation therapy (RT), has been long established as an effective means of local tumor control. RT can be delivered to inoperable lesions or to those with non-benign histology and for Simpson I-III and IV-V resection. RT can be delivered with photons or particles (protons or carbon ions) in stereotactic or non-stereotactic conditions. Particle therapy delivered for these tumors uses the physical properties of charged carbon ions or protons to spare normal brain tissue (i.e. Bragg peak), with or without or a dose-escalation paradigm for non-benign lesions. PT can substantially decrease the dose delivered to the non-target brain tissues, including but not limited to the hippocampi, optic apparatus or cochlea. Only a limited number of meningioma patients have been treated with PT in the adjuvant or recurrent setting, as well as for inoperable lesions with pencil beam scanning and with protons only. Approximately 500 patients with image-defined or WHO grade I meningioma have been treated with protons. The reported outcome, usually 5-year local tumor control, ranges from 85 to 99% (median, 96%). For WHO grade II or III patients, the outcome of only 97 patients has been published, reporting a median tumor local control rate of 52% (range, 38-71.1). Only 24 recurring patients treated previously with photon radiotherapy and re-treated with PT were reported. The clinical outcome of these challenging patients seems interesting, provided that they presented initially with benign tumors, are not in the elderly category and have been treated previously with conventional radiation dose of photons. Overall, the number of meningioma patients treated or-re-irradiated with this treatment modality is small and the clinical evidence level is somewhat low (i.e. 3b-5). In this review, we detail the results of upfront PT delivered to patients with meningioma in the adjuvant setting and for inoperable tumors. The outcome of meningioma patients treated with this radiation modality for recurrent tumors, with or without previous RT, will also be reviewed.
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http://dx.doi.org/10.3389/fonc.2020.558845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769250PMC
December 2020

Liver-ultrasound-guided lung tumour tracking for scanned proton therapy: a feasibility study.

Phys Med Biol 2021 01 26;66(3):035011. Epub 2021 Jan 26.

Center for Proton Therapy, Paul Scherrer Institute (PSI), Villigen PSI, Switzerland.

Pencil beam scanned (PBS) proton therapy of lung tumours is hampered by respiratory motion and the motion-induced density changes along the beam path. In this simulation study, we aim to investigate the effectiveness of proton beam tracking for lung tumours both under ideal conditions and in conjunction with a respiratory motion model guided by real-time ultrasound imaging of the liver. Multiple-breathing-cycle 4DMRIs of the thorax and abdominal 2D ultrasound images were acquired simultaneously for five volunteers. Deformation vector fields extracted from the 4DMRI, referred to as ground truth motion, were used to generate 4DCT(MRI) data sets of two lung cancer patients, resulting in 10 data sets with variable motion patterns. Given the 4DCT(MRI) and the corresponding ultrasound images as surrogate data, a patient-specific motion model was built. The model consists of an autoregressive model and Gaussian process regression for the temporal and spatial prediction, respectively. Two-field PBS plans were optimised on the reference CTs, and 4D dose calculations (4DDC) were used to simulate dose delivery for (a) unmitigated motion, (b) ideal 2D and 3D tracking (both beam adaption and 4DDC based on ground truth motion), and (c) realistic 2D and 3D tracking (beam adaption based on motion predictions, 4DDC on ground truth motion). Model-guided tracking retrieved clinically acceptable target dose homogeneity, as seen in a substantial reduction of the D5%-D95% compared to the non-mitigated simulation. Tracking in 2D and 3D resulted in a similar improvement of the dose homogeneity, as did ideal and realistic tracking simulations. In some cases, however, the tracked deliveries resulted in a shift towards higher or lower dose levels, leading to unacceptable target over- or under-coverage. The presented motion modelling framework was shown to be an accurate motion prediction tool for the use in proton beam tracking. Tracking alone, however, may not always effectively mitigate motion effects, making it necessary to combine it with other techniques such as rescanning.
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http://dx.doi.org/10.1088/1361-6560/abcde6DOI Listing
January 2021

Dosimetric analysis of local failures in skull-base chordoma and chondrosarcoma following pencil beam scanning proton therapy.

Radiat Oncol 2020 Nov 16;15(1):266. Epub 2020 Nov 16.

Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Forschungsstrasse 111, 5232, Villigen, Switzerland.

Background: Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis.

Methods: 222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2Gy. A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTV, PTV) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression.

Results: After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0-86%) for the GTV, 70% (range 0-100%) for PTV and 83% (range 0-100%) for PTV. In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66Gy, p = 0.01), GTV(volume, p = 0.02), PTV(max, p = 0.02), PTV(V < 66Gy, p = 0.03), PTV(V < 59Gy, p = 0.02), PTV(volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTV(volume, p = 0.05) and GTV(V < 66Gy, p = 0.02) were independent prognostic factors for LR.

Conclusion: This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma.
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http://dx.doi.org/10.1186/s13014-020-01711-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670611PMC
November 2020

Good long-term visual outcomes of parapapillary choroidal melanoma patients treated with proton therapy: a comparative study.

Int Ophthalmol 2021 Feb 25;41(2):441-452. Epub 2020 Sep 25.

Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.

Purpose: To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years.

Methods: This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years.

Results: Mean follow-up was 120.8 ± 48.8 months (54.0-295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the "good visual outcome" (GVO) group, while the remaining 246 (79%) constituted the "poor visual outcome" (PVO) group, subdivided into 70 (22%) with a VA of 0.3-1.0 logMAR (0.1-0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (< 0.1 decimal). On multivariate analysis, older age (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P < 0.03), volume of the optic disc and macula receiving 50% of dose (30 CGE) (P = 0.02 and P < 0.001, respectively) were independent negative predictors of GVO.

Conclusions: Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.
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http://dx.doi.org/10.1007/s10792-020-01594-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882567PMC
February 2021

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

Pediatr Blood Cancer 2020 12 2;67(12):e28664. Epub 2020 Sep 2.

Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.

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.
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http://dx.doi.org/10.1002/pbc.28664DOI Listing
December 2020

Commissioning and quality assurance of a novel solution for respiratory-gated PBS proton therapy based on optical tracking of surface markers.

Z Med Phys 2022 Feb 20;32(1):52-62. Epub 2020 Aug 20.

Center for Proton Therapy, Paul Scherrer Institute, 5232 Villigen, Switzerland.

We present the commissioning and quality assurance of our clinical protocol for respiratory gating in pencil beam scanning proton therapy for cancer patients with moving targets. In a novel approach, optical tracking has been integrated in the therapy workflow and used to monitor respiratory motion from multiple surrogates, applied on the patients' chest. The gating system was tested under a variety of experimental conditions, specific to proton therapy, to evaluate reaction time and reproducibility of dose delivery control. The system proved to be precise in the application of beam gating and allowed the mitigation of dose distortions even for large (1.4cm) motion amplitudes, provided that adequate treatment windows were selected. The total delivered dose was not affected by the use of gating, with measured integral error within 0.15cGy. Analysing high-resolution images of proton transmission, we observed negligible discrepancies in the geometric location of the dose as a function of the treatment window, with gamma pass rate greater than 95% (2%/2mm) compared to stationary conditions. Similarly, pass rate for the latter metric at the 3%/3mm level was observed above 97% for clinical treatment fields, limiting residual movement to 3mm at end-exhale. These results were confirmed in realistic clinical conditions using an anthropomorphic breathing phantom, reporting a similarly high 3%/3mm pass rate, above 98% and 94%, for regular and irregular breathing, respectively. Finally, early results from periodic QA tests of the optical tracker have shown a reliable system, with small variance observed in static and dynamic measurements.
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http://dx.doi.org/10.1016/j.zemedi.2020.07.001DOI Listing
February 2022

Liver-ultrasound based motion modelling to estimate 4D dose distributions for lung tumours in scanned proton therapy.

Phys Med Biol 2020 12 22;65(23):235050. Epub 2020 Dec 22.

Department of Biomedical Engineering, University of Basel, Allschwil, Switzerland.

Motion mitigation strategies are crucial for scanned particle therapy of mobile tumours in order to prevent geometrical target miss and interplay effects. We developed a patient-specific respiratory motion model based on simultaneously acquired time-resolved volumetric MRI and 2D abdominal ultrasound images. We present its effects on 4D pencil beam scanned treatment planning and simulated dose distributions. Given an ultrasound image of the liver and the diaphragm, principal component analysis and Gaussian process regression were applied to infer dense motion information of the lungs. 4D dose calculations for scanned proton therapy were performed using the estimated and the corresponding ground truth respiratory motion; the differences were compared by dose difference volume metrics. We performed this simulation study on 10 combined CT and 4DMRI data sets where the motion characteristics were extracted from 5 healthy volunteers and fused with the anatomical CT data of two lung cancer patients. Median geometrical estimation errors below 2 mm for all data sets and maximum dose differences of [Formula: see text] = 43.2% and [Formula: see text] = 16.3% were found. Moreover, it was shown that abdominal ultrasound imaging allows to monitor organ drift. This study demonstrated the feasibility of the proposed ultrasound-based motion modelling approach for its application in scanned proton therapy of lung tumours.
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http://dx.doi.org/10.1088/1361-6560/abaa26DOI Listing
December 2020

Clinical outcomes of head and neck adenoid cystic carcinoma patients treated with pencil beam-scanning proton therapy.

Oral Oncol 2020 08 12;107:104752. Epub 2020 May 12.

Center for Proton Therapy, Paul Scherrer Institute, Villigen PSI, Switzerland; Radiation Oncology Department, University Hospital Zürich, Zürich, Switzerland; Radiation Oncology Department, University Hospital Bern, Inselspital, Bern, Switzerland. Electronic address:

Objective: The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution.

Materials And Methods: Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed.

Results: The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed.

Conclusions: PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104752DOI Listing
August 2020

Pencil beam scanning proton therapy for the treatment of craniopharyngioma complicated with radiation-induced cerebral vasculopathies: A dosimetric and linear energy transfer (LET) evaluation.

Radiother Oncol 2020 08 5;149:197-204. Epub 2020 May 5.

Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland; Department of Radiation Oncology, University Hospital of Zürich, Zürich, Switzerland; Department of Radiation Oncology, University Hospital of Bern, Bern, Switzerland.

Background And Purpose: This study analyses the dosimetric and dose averaged Linear Energy transfer (LETd) correlation in paediatric craniopharyngioma (CP) patients with and without radiation-induced cerebral vasculopathies (RICVs) treated with pencil beam scanning (PBS) proton therapy (PT).

Material And Methods: We reviewed a series of 16 CP patients treated with PT to a median dose of 54 Gy(RBE). Two (12.5%) index patients presented RICVs 14 and 24 months (median, 19) after PT. Organs at risks (OARs) as bilateral internal carotid arteries (ICAs) and circle of Willis were contoured based on CTs and MRIs pre- and post-PT. Dosimetry was reviewed and LETd distributions were calculated; LETd metric for PTVs and OARs were analysed. For a sub-cohort, dosimetric and LETd values robustness due to range uncertainties were computed.

Results: For the two index patients, no correlation was observed between RICVs and OARs doses. However for those patients mean(maximum) LETd values in the affected OARs were up to 4.0 ± 0.4 (7.8 ± 0.1)keV/μm; those LETd values were significantly higher (p = 0.02) than the mean(maximum) LETd values for the rest of the cohort (mean: 3.1 ± 0.3, maximum: 4.8 ± 1.0 keV/μm). This was due to asymmetric field arrangement, thus resulting in marked asymmetric LETd distributions. For such arrangement, maximum LETd values variations in vascular structures due to range uncertainties were up to 1.2 keV/μm, whilst for the symmetric one they were up to 0.7 keV/μm.

Conclusions: For children with and without RICVs, quantitative analysis showed a significant correlation with LETd average/maximum values in vascular structures, whilst no correlation was found on dosimetric parameters.
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http://dx.doi.org/10.1016/j.radonc.2020.04.052DOI Listing
August 2020

Prognostic impact of the "Sekhar grading system for cranial Chordomas" in patients treated with pencil beam scanning proton therapy: an institutional analysis.

Radiat Oncol 2020 May 6;15(1):96. Epub 2020 May 6.

Center for Proton Therapy, Paul Scherrer Institute, 5232 PSI West, Villigen, Switzerland.

Background: Skull base chordomas are rare and heterogeneously behaving tumors. Though still classified as benign they can grow rapidly, are locally aggressive, and have the potential to metastasize. To adapt the treatment to the specific needs of patients at higher risk of recurrence, a pre-proton therapy prognostic grading system would be useful. The aim of this retrospective analysis is to assess prognostic factors and the "Sekhar Grading System for Cranial Chordomas" (SGSCC) by evaluating the larger cohort of patients treated at our institution as to determine its reproducibility and ultimately to ensure more risk adapted local treatments for these challenging tumors.

Methods: We analyzed 142 patients treated for skull base chordomas between 2004 and 2016. We focused the analysis on the 5 criteria proposed for the SGSCC (tumor size, number of anatomic regions and vessels involved, intradural invasion, as well as recurrence after prior treatment) and classified our patients according to their score (based on the above mentioned criteria) into three prognostic groups, low-risk, intermediate-risk and high-risk. The three groups were then analyzed in regards of local control, local recurrence-free survival and overall survival.

Results: The median follow up was 52 months (range, 3-152). We observed 34 (24%) patients with a local recurrence, resulting in a local control of 75% at 5 years. Overall survival was 83% at 5 years, 12 (9%) patients had died due to local progression. When split into the three prognostic groups according to the SGSCC the observed local control was 90, 72 and 64% (p = 0.07) in the low-, intermediate- and high-risk group, respectively. A similar correlation was observed for local recurrence-free survival with 93, 89 and 66% (p = 0.05) and for overall survival with 89, 83 and 76% (p = 0.65) for the same prognostic groups.

Conclusions: After splitting our patient cohort into the three SGSCC risk groups, we found a trend towards better outcome for those patients with lower as opposed to higher scores. These results suggest that this prognostic grading system published by Sekhar et al. could be integrated in the management decision-tree for patients with skull base chordoma.
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http://dx.doi.org/10.1186/s13014-020-01547-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201750PMC
May 2020

Practice Considerations for Proton Beam Radiation Therapy of Uveal Melanoma During the Coronavirus Disease Pandemic: Particle Therapy Co-Operative Group Ocular Experience.

Adv Radiat Oncol 2020 Jul-Aug;5(4):682-686. Epub 2020 Apr 23.

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Uveal melanoma (UM) is a rare but life-threatening cancer of the eye. In light of the coronavirus disease (COVID-19) pandemic, hospitals and proton eye therapy facilities must analyze several factors to ensure appropriate treatment protocols for patients and provider teams. Practice considerations to limit COVID-19 transmission in the proton ocular treatment setting for UM are necessary. The Particle Therapy Co-Operative Group is the largest international community of particle/proton therapy providers. Participating experts have current or former affiliation with the member institutions of the Particle Therapy Co-Operative Group Ocular subcommittee with long-standing high-volume proton ocular programs. The practices reviewed in this document must be taken in conjunction with local hospital procedures, multidisciplinary recommendations, and regional/national guidelines, as each community may have its unique needs, supplies, and protocols. Importantly, as the pandemic evolves, so will the strategies and recommendations. Given the unique circumstances for UM patients, along with indications of potential ophthalmologic transmission as a result of health care providers working in close proximity to patients and intrinsic infectious risk from eyelashes, tears, and hair, practice strategies may be adapted to reduce the risk of viral transmission. Certainly, providers and health care systems will continue to examine and provide as safe and effective care as possible for patients in the current environment.
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http://dx.doi.org/10.1016/j.adro.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179507PMC
April 2020

The European Organisation for Research and Treatment of Cancer, State of Science in radiation oncology and priorities for clinical trials meeting report.

Eur J Cancer 2020 05 16;131:76-88. Epub 2020 Apr 16.

Paul Scherrer Institute, ETH Domain, Villigen, Switzerland.

Background: New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers.

Methods: Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development.

Conclusions: Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology.
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http://dx.doi.org/10.1016/j.ejca.2020.02.050DOI Listing
May 2020

Particle therapy in Europe.

Mol Oncol 2020 07 22;14(7):1492-1499. Epub 2020 Apr 22.

Paul Scherrer Institute, Villigen, Switzerland.

Particle therapy using protons or heavier ions is currently the most advanced form of radiotherapy and offers new opportunities for improving cancer care and research. Ions deposit the dose with a sharp maximum - the Bragg peak - and normal tissue receives a much lower dose than what is delivered by X-ray therapy. Particle therapy has also biological advantages due to the high linear energy transfer of the charged particles around the Bragg peak. The introduction of particle therapy has been slow in Europe, but within the last decade, more than 20 clinical facilities have opened and facilitated access to this frontline therapy. In this review article, the basic concepts of particle therapy are reviewed along with a presentation of the current clinical indications, the European clinical research, and the established networks.
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http://dx.doi.org/10.1002/1878-0261.12677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332216PMC
July 2020

Shortening delivery times for intensity-modulated proton therapy by reducing the number of proton spots: an experimental verification.

Phys Med Biol 2020 05 11;65(9):095008. Epub 2020 May 11.

Center for Proton Therapy, Paul Scherrer Institute, Villigen PSI, Switzerland.

Delivery times of intensity-modulated proton therapy (IMPT) can be shortened by reducing the number of spots in the treatment plan, but this may affect clinical plan delivery. Here, we assess the experimental deliverability, accuracy and time reduction of spot-reduced treatment planning for a clinical case, as well as its robustness. For a single head-and-neck cancer patient, a spot-reduced plan was generated and compared with the conventional clinical plan. The number of proton spots was reduced using the iterative 'pencil beam resampling' technique. This involves repeated inverse optimization, while adding in each iteration a small sample of randomly selected spots and subsequently excluding low-weighted spots until plan quality deteriorates. Field setup was identical for both plans and comparable dosimetric quality was a prerequisite. Both IMPT plans were delivered on PSI Gantry 2 and measured in water, while delivery log-files were used to extract delivery times and reconstruct the delivered dose via Monte-Carlo dose calculations. In addition, robustness simulations were performed to assess sensitivity to machine inaccuracies and errors in patient setup and proton range. The number of spots was reduced by 96% (from 33 855 to 1510 in total) without compromising plan quality. The spot-reduced plan was deliverable on our gantry in standard clinical mode and resulted in average delivery times per field being shortened by 46% (from 51.2 to 27.6 s). For both plans, differences between measured and calculated dose were within clinical tolerance for patient-specific verifications and Monte-Carlo dose reconstructions were in accordance with clinical experience. The spot-reduced plan was slightly more sensitive to machine inaccuracies, but more robust against setup and range errors. In conclusion, for an example head-and-neck case, spot-reduced IMPT planning provided a deliverable treatment plan and enabled considerable shortening of the delivery time (∼50%) without compromising plan quality or delivery accuracy, and without substantially affecting robustness.
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http://dx.doi.org/10.1088/1361-6560/ab7e7cDOI Listing
May 2020
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