Clinical implementations of 4D pencil beam scanned particle therapy: Report on the 4D treatment planning workshop 2016 and 2017

In 2016 and 2017, the 8th and 9th 4D treatment planning workshop took place in Groningen (the Netherlands) and Vienna (Austria), respectively. This annual workshop brings together international experts to discuss research, advances in clinical implementation as well as problems and challenges in 4D treatment planning, mainly in spot scanned proton therapy. In the last two years several aspects like treatment planning, beam delivery, Monte Carlo simulations, motion modeling and monitoring, QA phantoms as well as 4D imaging were thoroughly discussed.This report provides an overview of discussed topics, recent findings and literature review from the last two years. Its main focus is to highlight translation of 4D research into clinical practice and to discuss remaining challenges and pitfalls that still need to be addressed and to be overcome.     

Required transition from research to clinical application: Report on the 4D treatment planning workshops 2014 and 2015

Since 2009, a 4D treatment planning workshop has taken place annually, gathering researchers working on the treatment of moving targets, mainly with scanned ion beams. Topics discussed during the workshops range from problems of time resolved imaging, the challenges of motion modelling, the implementation of 4D capabilities for treatment planning, up to different aspects related to 4D dosimetry and treatment verification.This report gives an overview on topics discussed at the 4D workshops in 2014 and 2015. It summarizes recent findings, developments and challenges in the field and discusses the relevant literature of the recent years. The report is structured in three parts pointing out developments in the context of understanding moving geometries, of treating moving targets and of 4D quality assurance (QA) and 4D dosimetry.The community represented at the 4D workshops agrees that research in the context of treating moving targets with scanned ion beams faces a crucial phase of clinical translation. In the coming years it will be important to define standards for motion monitoring, to establish 4D treatment planning guidelines and to develop 4D QA tools. These basic requirements for the clinical application of scanned ion beams to moving targets could e.g. be determined by a dedicated ESTRO task group.Besides reviewing recent research results and pointing out urgent needs when treating moving targets with scanned ion beams, the report also gives an outlook on the upcoming 4D workshop organized at the University Medical Center Groningen (UMCG) in the Netherlands at the end of 2016.     

Clinical practice vs. state-of-the-art research and future visions: Report on the 4D treatment planning workshop for particle therapy – Edition 2018 and 2019

The 4D Treatment Planning Workshop for Particle Therapy, a workshop dedicated to the treatment of moving targets with scanned particle beams, started in 2009 and since then has been organized annually. The mission of the workshop is to create an informal ground for clinical medical physicists, medical physics researchers and medical doctors interested in the development of the 4D technology, protocols and their translation into clinical practice. The 10th and 11th editions of the workshop took place in Sapporo, Japan in 2018 and Krakow, Poland in 2019, respectively.This review report from the Sapporo and Krakow workshops is structured in two parts, according to the workshop programs. The first part comprises clinicians and physicists review of the status of 4D clinical implementations. Corresponding talks were given by speakers from five centers around the world: Maastro Clinic (The Netherlands), University Medical Center Groningen (The Netherlands), MD Anderson Cancer Center (United States), University of Pennsylvania (United States) and The Proton Beam Therapy Center of Hokkaido University Hospital (Japan). The second part is dedicated to novelties in 4D research, i.e. motion modelling, artificial intelligence and new technologies which are currently being investigated in the radiotherapy field.     

First-in-human imaging using a MR-compatible e4D ultrasound probe for motion management of radiotherapy

PurposeRespiration-induced tumor or organ positional changes can impact the accuracy of external beam radiotherapy. Motion management strategies are used to account for these changes during treatment. The authors report on the development, testing, and first-in-human evaluation of an electronic 4D (e4D) MR-compatible ultrasound probe that was designed for hands-free operation in a MR and linear accelerator (LINAC) environment.MethodsUltrasound components were evaluated for MR compatibility. Electromagnetic interference (EMI) shielding was used to enclose the entire probe and a factory-fabricated cable shielded with copper braids was integrated into the probe. A series of simultaneous ultrasound and MR scans were acquired and analyzed in five healthy volunteers.ResultsThe ultrasound probe led to minor susceptibility artifacts in the MR images immediately proximal to the ultrasound probe at a depth of <10 mm. Ultrasound and MR-based motion traces that were derived by tracking the salient motion of endogenous target structures in the superior-inferior (SI) direction demonstrated good concordance (Pearson correlation coefficients of 0.95–0.98) between the ultrasound and MRI datasets.ConclusionWe have demonstrated that our hands-free, e4D probe can acquire ultrasound images during a MR acquisition at frame rates of approximately 4 frames per second (fps) without impacting either the MR or ultrasound image quality. This use of this technology for interventional procedures (e.g. biopsies and drug delivery) and motion compensation during imaging are also being explored.     

3D dosimetric validation of ultrasound-guided radiotherapy with a dynamically deformable abdominal phantom

ObjectivesThe purpose of this study was to dosimetrically benchmark gel dosimetry measurements in a dynamically deformable abdominal phantom for intrafraction image guidance through a multi-dosimeter comparison. Once benchmarked, the study aimed to perform a proof-of-principle study for validation measurements of an ultrasound image-guided radiotherapy delivery system.MethodsThe phantom was dosimetrically benchmarked by delivering a liver VMAT plan and measuring the 3D dose distribution with DEFGEL dosimeters. Measured doses were compared to the treatment planning system and measurements acquired with radiochromic film and an ion chamber. The ultrasound image guidance validation was performed for a hands-free ultrasound transducer for the tracking of liver motion during treatment.ResultsGel dosimeters were compared to the TPS and film measurements, showing good qualitative dose distribution matches, low γ values through most of the high dose region, and average 3%/5 mm γ-analysis pass rates of 99.2%(0.8%) and 90.1%(0.8%), respectively. Gel dosimeter measurements matched ion chamber measurements within 3%. The image guidance validation study showed the measurement of the treatment delivery improvements due to the inclusion of the ultrasound image guidance system. Good qualitative matching of dose distributions and improvements of the γ-analysis results were observed for the ultrasound-gated dosimeter compared to the ungated dosimeter.ConclusionsDEFGEL dosimeters in phantom showed good agreement with the planned dose and other dosimeters for dosimetric benchmarking. Ultrasound image guidance validation measurements showed good proof-of-principle of the utility of the phantom system as a method of validating ultrasound-based image guidance systems and potentially other image guidance methods.     

Tridimensional dose evaluation of the respiratory motion influence on breast radiotherapy treatments using conformal radiotherapy,forward IMRT,and inverse IMRT planning techniques

PurposeTo evaluate the respiratory motion influence on the tridimensional (3D) dose delivery to breast-shaped phantoms using conformal radiotherapy (3D-RT), Field-in Field (FiF), and IMRT planning techniques.MethodsThis study used breast-shaped phantoms filled with MAGIC-f gel dosimeter to simulate the breast, and an oscillation platform to simulate the respiratory motion. The platform allowed motion in the anterior-posterior direction with oscillation amplitudes of 0.34 cm, 0.88 cm, and 1.22 cm. CT images of the static phantom were used for the 3D-RT, FiF, and IMRT treatment planning. Five phantoms were prepared and irradiated for each planning technique evaluated. Phantom 1 was irradiated static, phantoms 2–4 were irradiated moving with the three different motion amplitudes, and phantom 5 was used as a reference. The 3D dose distributions were obtained by relaxometry of magnetic resonance imaging, and the respiratory motion influence in the doses distribution was accessed by gamma evaluations (3%/3mm/15% threshold) comparing the measurements of the phantoms irradiated under movement with the static ones.ResultsThe mean gamma approvals for three oscillatory amplitudes were 96.44%, 93.23%, and 91.65%; 98.42%, 95.66%, and 94.31%; and 94.49%, 93.51%, and 86.62% respectively for 3D-RT, FiF and IMRT treatments. A gamma results profile per slice along the phantom showed that for FiF and IMRT irradiations, most of the failures occurred in the central region of the phantom.ConclusionsBy increasing the respiratory motion movement, the dose distribution variations for the three planning techniques were more pronounced, being the FiF technique variations the smallest one.     

Visualization of Endosome Dynamics in Living Nerve Terminals with Four-dimensional Fluorescence Imaging

Four-dimensional (4D) light imaging has been used to study behavior of small structures within motor nerve terminals of the thin transversus abdominis muscle of the garter snake. Raw data comprises time-lapse sequences of 3D z-stacks. Each stack contains 4-20 images acquired with epifluorescence optics at focal planes separated by 400-1,500 nm. Steps in the acquisition of image stacks, such as adjustment of focus, switching of excitation wavelengths, and operation of the digital camera, are automated as much as possible to maximize image rate and minimize tissue damage from light exposure. After acquisition, a set of image stacks is deconvolved to improve spatial resolution, converted to the desired 3D format, and used to create a 4D "movie" that is suitable for variety of computer-based analyses, depending upon the experimental data sought. One application is study of the dynamic behavior of two classes of endosomes found in nerve terminals-macroendosomes (MEs) and acidic endosomes (AEs)-whose sizes (200-800 nm for both types) are at or near the diffraction limit. Access to 3D information at each time point provides several advantages over conventional time-lapse imaging. In particular, size and velocity of movement of structures can be quantified over time without loss of sharp focus. Examples of data from 4D imaging reveal that MEs approach the plasma membrane and disappear, suggesting that they are exocytosed rather than simply moving vertically away from a single plane of focus. Also revealed is putative fusion of MEs and AEs, by visualization of overlap between the two dye-containing structures as viewed in each three orthogonal projections.     

Evaluation of residual abdominal tumour motion in carbon ion gated treatments through respiratory motion modelling

At the Italian National Centre for Oncologic Hadrontherapy (CNAO) patients with upper-abdominal tumours are being treated with carbon ion therapy, adopting the respiratory gating technique in combination with layered rescanning and abdominal compression to mitigate organ motion. Since online imaging of the irradiated volume is not feasible, this study proposes a modelling approach for the estimation of residual motion of the target within the gating window. The model extracts a priori respiratory motion information from the planning 4DCT using deformable image registration (DIR), then combines such information with the external surrogate signal recorded during dose delivery. This provides estimation of a CT volume corresponding to any given respiratory phase measured during treatment. The method was applied for the retrospective estimation of tumour residual motion during irradiation, considering 16 patients treated at CNAO with the respiratory gating protocol. The estimated tumour displacement, calculated with respect to the reference end-exhale position, was always limited (average displacement is 0.32 ± 0.65 mm over all patients) and below the maximum motion defined in the treatment plan. This supports the hypothesis of target position reproducibility, which is the crucial assumption in the gating approach. We also demonstrated the use of the model as a simulation tool to establish a patient-specific relationship between residual motion and the width of the gating window. In conclusion, the implemented method yields an estimation of the repeatability of the internal anatomy configuration during gated treatments, which can be used for further studies concerning the dosimetric impact of the estimated residual organ motion.     

Geometric inaccuracy and co-registration errors for CT,DynaCT and MRI images used in robotic stereotactic radiosurgery treatment planning

PurposeTo measure the combined errors due to geometric inaccuracy and image co-registration on secondary images (dynamic CT angiography (dCTA), 3D DynaCT angiography (DynaCTA), and magnetic resonance images (MRI)) that are routinely used to aid in target delineation and planning for stereotactic radiosurgery (SRS).MethodsThree phantoms (one commercial and two in-house built) and two different analysis approaches (commercial and MATLAB based) were used to quantify the magnitude of geometric image distortion and co-registration errors for different imaging modalities within CyberKnife’s MultiPlan treatment planning software. For each phantom, the combined errors were reported as a mean target registration error (TRE). The mean TRE’s for different intramodality imaging parameters (e.g., mAs, kVp, and phantom set-ups) and for dCTA, DynaCTA, and MRI systems were measured.ResultsOnly X-ray based imaging can be performed with the commercial phantom, and the mean TRE ± standard deviation values were large compared to the in-house analysis using MATLAB. With the 3D printed phantom, even drastic changes in treatment planning CT imaging protocols did not greatly influence the mean TRE (<0.5 mm for a 1 mm slice thickness CT). For all imaging modalities, the largest mean TRE was found on DynaCT, followed by T2-weighted MR images (albeit all <1 mm).ConclusionsThe user may overestimate the mean TRE if the commercial phantom and MultiPlan were used solely. The 3D printed phantom design is a sensitive and suitable quality assurance tool for measuring 3D geometric inaccuracy and co-registration errors across all imaging modalities.     

Dose delivery accuracy on helical tomotherapy for 4-dimensional tumor motion — a phantom study

BackgroundThe advances in image guidance and capability of highly conformal dose deliveries made possible the use of helical tomotherapy (HT) for lung cancer treatment. To determine the effect of respiratory motion on the delivered dose in HT, film dosimetry using a dynamic phantom was performed. This was a phantom study to determine the effect of motion on the delivered dose in HT.Materials and methods4D computed tomography (4DCT) was acquired for various target motions of CIRS dynamic phantom (CIRS Inc., Norfolk, USA) with 2.5cm diameter spherical target of volume 8.2 cc moving in the COS⁴ motion pattern. AveIP images and treatment plans were generated in the HT planning system. Target excursions during treatment delivery were changed in the superior-inferior, anteroposterior and lateral directions. The breathing cycle time was varied from 4 to 5 sec. and also the delivery interruptions were introduced. A film was exposed for each delivery and gamma analysis was performed.ResultsThe gamma pass rate (GPR) with 3%, 2 mm criteria for the target motion in the S-I direction showed a significant reduction from 97.5% to 54.4% as the motion increased from 3 mm to 8 mm (p = 0.03). For the target motion in S-I = 8 mm, L-R = A-P = 3 mm, the percentage decrease in the GPR was 74% (p = 0.001) for three interruptions.ConclusionThe ITV based approach in HT is ideal for a shallow breathing situation when the tumor excursions were confined to 5 mm in the S-I and 3 mm in L-R and A-P directions.     

A modular dose delivery system for treating moving targets with scanned ion beams: Performance and safety characteristics,and preliminary tests

PurposeThe purpose of this study was to develop a modular dose-delivery system (DDS) for scanned-ion radiotherapy that mitigates against organ motion artifacts by synchronizing the motion of the beam with that of the moving anatomy.MethodsWe integrated a new motion synchronization system and an existing DDS into two centers. The modular approach to integration utilized an adaptive layer of software and hardware interfaces. The method of synchronization comprised three major tasks, namely, the creation of 3D treatment plans (each representing one phase of respiratory motion and together comprising a 4D plan), monitoring anatomic motion during treatment, and synchronization of the beam to anatomic motion. The synchronization was accomplished in real time by repeatedly selecting and delivering a 3D plan, i.e., the one that most closely corresponded to the current anatomic state, until all plans were delivered. The performance characteristics of the motion mitigation system were tested by delivering 4D treatment plans to a moving phantom and comparing planned and measured dose distributions. Dosimetric performance was considered acceptable when the gamma-index pass rate was >90%, homogeneity-index value was >95%, and conformity-index value was >60%. Selected safety characteristics were tested by introducing errors during treatment and testing DDS response.ResultsAcceptable dosimetric performance and safety characteristics were observed for all treatment plans.ConclusionsWe demonstrated, for the first time, that a modular prototype system, synchronizing scanned ion beams with moving targets can deliver conformal, motion-compensated dose distributions. The prototype system was implemented and characterized at GSI and CNAO.     

功能与分子影像在头颈部肿瘤放射治疗计划和疗效评价中的应用

目前临床普遍采用功能与分子影像检测手段能来评价头颈部肿瘤的放射治疗计划和疗效,可指导个体化治疗从而提高疗效。文章概述了功能与分子影像技术CT,MRI,PET-CT,超声检测技术在头颈部肿瘤放射治疗计划制定和疗效评价中的应用进展。结果显示,不同分子影像检测方法如在检查时机的选择、诊断和鉴别诊断的价值、观察放射治疗后肿瘤的残存和复发、预测放射治疗效果、指导后续治疗等方面均可起到重要作用。采用图像融合技术进行联合应用,如PET-CT和MRI-CT等,可提高检测的准确率。临床医生需在常规影像学手段的基础上,根据头颈部肿瘤患者病情和治疗方法的不同选用正确的功能和分子影像检测手段,更好地指导制定放射治疗计划及综合评价放射治疗后的疗效。     

Intérêt des traceurs de l’hypoxie en radiothérapie

Tumor hypoxia is a major parameter of radioresistance. Hypoxia PET imaging using several radiotracers (F-Miso, FAZA, Cu-ATSM, EF5…) may help predict response to radiotherapy. Hypoxic area evaluation may also help select patients for hypoxia-targeting drugs, and thus reinforcing radiotherapy effects. Hypoxia imaging may also be fused with radiotherapy planning CT to define radioresistance areas that may be boosted by dose-painting radiotherapy. Despite several difficulties (patient positioning, organ and tumor motion, image definition…), targeting hypoxic regions within tumors is one of the most promising research strategies of modern radiotherapy.     

A review of deep learning based methods for medical image multi-organ segmentation

Deep learning has revolutionized image processing and achieved the-state-of-art performance in many medical image segmentation tasks. Many deep learning-based methods have been published to segment different parts of the body for different medical applications. It is necessary to summarize the current state of development for deep learning in the field of medical image segmentation. In this paper, we aim to provide a comprehensive review with a focus on multi-organ image segmentation, which is crucial for radiotherapy where the tumor and organs-at-risk need to be contoured for treatment planning. We grouped the surveyed methods into two broad categories which are ‘pixel-wise classification’ and ‘end-to-end segmentation’. Each category was divided into subgroups according to their network design. For each type, we listed the surveyed works, highlighted important contributions and identified specific challenges. Following the detailed review, we discussed the achievements, shortcomings and future potentials of each category. To enable direct comparison, we listed the performance of the surveyed works that used thoracic and head-and-neck benchmark datasets.     

Imaging opportunities for treatment planning in intraoperative electron beam radiotherapy (IOERT): Developments in the context of RADIANCE system

AimThe purpose of this report is to store the information of the pre-planning and compare this data with the actual data of the procedure.BackgroundCurrently, intraoperative electron beam radiotherapy clinical practice lacks a treatment planning system.Materials and methodsThe RADIANCE concept approaches treatment planning by providing the user with a navigation platform based on a three-dimensional imaging system in which the radiation oncologist can target the tumor and risk areas in different sections (axial, coronal, sagittal), while a volume rendering engine displays a 3D image that is automatically updated as we make any changes of the space. Finally, the user may select the parameters of the applicator, energy and dose of treatment to optimize the procedure. Six cases are clinically described and illustrated.ResultsRADIANCE is a useful tool in planning IOERT. Tumor segmentation and risk areas with minimal guide in the selection of parameters for the applicator. Complex locations are challenging, where the experience and skill of the radiation oncologist is necessary to optimize the process. New developments include imaging innovated uses. Intraoperative imaging will approach reality and allow real time, dosimetry estimations, stereotactic recognition of patient and tumor bed position, will guide automatization of radiation beam recognition and pre-robotic arrangements with linear accelerator movements.ConclusionsRADIANCE offers a new imaging expansion for IOERT, in the context of a multidisciplinary approach to optimize and define the treatment parameters to approximate the actual treatment radiotherapy procedure.     

Cine 4DCT imaging artifacts: Quantification and correlations with scanning parameters and target kinetics

To study temporal resolved computed tomography imaging (4-Dimensional Computed Tomography: 4DCT) artifacts correlations with scanning parameters and target kinetics and to assess uncertainty introduced by 4DCT in radiotherapy treatment planning.In this work we classified 4DCT artifacts as finite gantry rotation speed related (FGS) and finite sampling frequency related (FSF). We studied FGS artifacts using a respiratory phantom and FSF artifacts using a Monte Carlo simulation of acquisition timing.From our analysis FGS localization error is comparable with image resolution determined by voxel dimensions. Remaining FGS artifacts are correlated with gantry rotation time (Trot), target velocity (v) and their interaction.FSF artifacts occurrence is correlated with sampling ratio (SR), i.e. the ratio of patient respiratory period (Tresp) and sampling time (Ts).In the studied velocity range (0–2 cm/s), using a Trot of 0,5s and a SR higher than 15, FGS and FSF artifacts became comparable with other sources of uncertainty.Our considerations are valid for “ideal” breathing pattern only. When variations from periodical breathing, high target velocity (more than 2 cm/s) or high peak to peak amplitude (more than 2 cm) are present, patient specific images artifacts analysis is recommended.     

Treatment-integrated imaging,radiomics, and personalised radiotherapy: the future is at hand

Since the introduction of computed tomography for planning purposes in the 1970s, we have been observing a continuous development of different imaging methods in radiotherapy. The current achievements of imaging technologies in radiotherapy enable more than just improvement of accuracy on the planning stage. Through integrating imaging with treatment machines, they allow advanced control methods of dose delivery during the treatment. This article reviews how the integration of existing and novel forms of imaging changes radiotherapy and how these advances can allow a more individualised approach to cancer therapy.We believe that the significant challenge for the next decade is the continued integration of a range of different imaging devices into linear accelerators. These imaging modalities should show intra-fraction changes in body morphology and inter-fraction metabolic changes. As the use of these more advanced, integrated machines grows, radiotherapy delivery will become more accurate, thus resulting in better clinical outcomes: higher cure rates with fewer side effects.     

An international survey of imaging practices in radiotherapy

Improvements in delivery of radiation dose to target tissues in radiotherapy have increased the need for better image quality and led to a higher frequency of imaging patients. Imaging for treatment planning extends to function and motion assessment and devices are incorporated into medical linear accelerators (linacs) so that regions of tissue can be imaged at time of treatment delivery to ensure dose distributions are delivered as accurately as possible. A survey of imaging in 97 radiotherapy centres in nine countries on six continents has been undertaken with an on-line questionnaire administered through the International Commission on Radiological Protection mentorship programme to provide a snapshot of imaging practices. Responses show that all centres use CT for planning treatments and many utilise additional information from magnetic resonance imaging and positron emission tomography scans. Most centres have kV cone beam CT attached to at least some linacs and use this for the majority of treatment fractions. The imaging options available declined with the human development index (HDI) of the country, and the frequency of imaging during treatment depended more on country than treatment site with countries having lower HDIs imaging less frequently. The country with the lowest HDI had few kV imaging facilities and relied on MV planar imaging intermittently during treatment. Imaging protocols supplied by vendors are used in most centres and under half adapt exposure conditions to individual patients. Recording of patient doses, a knowledge of which is important in optimisation of imaging protocols, was limited primarily to European countries.     

Ultrasound-driven cardiac MRI

PurposeOne of the challenges of cardiac MR imaging is the compensation of respiratory motion, which causes the heart and the surrounding tissues to move. Commonly-used methods to overcome this effect, breath-holding and MR navigation, present shortcomings in terms of available acquisition time or need to periodically interrupt the acquisition, respectively. In this work, an implementation of respiratory motion compensation that obtains information from abdominal ultrasound and continuously adapts the imaged slice position in real time is presented.MethodsA custom workflow was developed, comprising an MR-compatible ultrasound acquisition system, a feature-motion-tracking system with polynomial predictive capability, and a custom MR sequence that continuously adapts the position of the acquired slice according to the tracked position. The system was evaluated on a moving phantom by comparing sharpness and image blurring between static and moving conditions, and in vivo by tracking the motion of the blood vessels of the liver to estimate the cardiac motion. Cine images of the heart were acquired during free breathing.ResultsIn vitro, the predictive motion correction yielded significantly better results than non-predictive or non-corrected acquisitions (p ≪ 0.01). In vivo, the predictive correction resulted in an image quality very similar to the breath-hold acquisition, whereas the uncorrected images show noticeable blurring artifacts.ConclusionIn this work, the possibility of using ultrasound navigation with tracking for the real-time adaptation of MR imaging slices was demonstrated. The implemented technique enabled efficient imaging of the heart with resolutions that would not be feasible in a single breath-hold.