A cellular automaton model for spheroid response to radiation and hyperthermia treatments.

Thermo-radiosensitisation is a promising approach for treatment of radio-resistant tumours such as those containing hypoxic subregions. Response prediction and treatment planning should account for tumour response heterogeneity, e.g. due to microenvironmental factors, and quantification of the biological effects induced. 3D tumour spheroids provide a physiological in vitro model of tumour response and a systems oncology framework for simulating spheroid response to radiation and hyperthermia is presented. Using a cellular automaton model, 3D oxygen diffusion, delivery of radiation and/or hyperthermia were simulated for many ([Formula: see text]) individual cells forming a spheroid. The iterative oxygen diffusion model was compared to an analytical oxygenation model and simulations were calibrated and validated against experimental data for irradiated (0-10 Gy) and/or heated (0-240 CEM43) HCT116 spheroids. Despite comparable clonogenic survival, spheroid growth differed significantly following radiation or hyperthermia. This dynamic response was described well by the simulation ([Formula: see text] > 0.85). Heat-induced cell death was implemented as a fast, proliferation-independent process, allowing reoxygenation and repopulation, whereas radiation was modelled as proliferation-dependent mitotic catastrophe. This framework stands out both through its experimental validation and its novel ability to predict spheroid response to multimodality treatment. It provides a good description of response where biological dose-weighting based on clonogenic survival alone was insufficient.

Beam selection for stereotactic ablative radiotherapy using Cyberknife with multileaf collimation.

The Cyberknife system (Accuray Inc., Sunnyvale, CA) enables radiotherapy using stereotactic ablative body radiotherapy (SABR) with a large number of non-coplanar beam orientations. Recently, a multileaf collimator has also been available to allow flexibility in field shaping. This work aims to evaluate the quality of treatment plans obtainable with the multileaf collimator. Specifically, the aim is to find a subset of beam orientations from a predetermined set of candidate directions, such that the treatment quality is maintained but the treatment time is reduced. An evolutionary algorithm is used to successively refine a randomly selected starting set of beam orientations. By using an efficient computational framework, clinically useful solutions can be found in several hours. It is found that 15 beam orientations are able to provide treatment quality which approaches that of the candidate beam set of 110 beam orientations, but with approximately half of the estimated treatment time. Choice of an efficient subset of beam orientations offers the possibility to improve the patient experience and maximise the number of patients treated.

Real-time energy/mass transfer mapping for online 4D dose reconstruction.

In this work we describe an ultra-fast, low-latency implementation of the energy/mass transfer (EMT) mapping method to accumulate dose on deforming geometries such as lung using the central processing unit (CPU). It enables the computation of the actually delivered dose for intensity-modulated radiation therapy on 4D image data in real-time at 25 Hz. In order to accumulate the delivered dose onto a reference phase a pre-calculated deformable vector field is used. The aim of this study is to present an online dose accumulation technique that can be carried out in less than 40 ms to accommodate the machine log update rate of our research linac. Three speed optimisation strategies for the CPU are discussed: single-core optimisation, parallelisation for multiple cores and vectorisation. The single-core implementation accumulates dose in about 1.1 s on a typical high resolution grid for a lung stereotactic body radiation therapy case. Adding parallelisation decreased the runtime to about 50 ms while adding vectorisation satisfied our real-time constraint by further reducing the dose accumulation time to 15 ms without compromising on resolution or accuracy. The presented method allows real-time dose accumulation on deforming patient geometries and has the potential to enable online dose evaluation and re-planning scenarios.

Online dose reconstruction for tracked volumetric arc therapy: Real-time implementation and offline quality assurance for prostate SBRT.

PURPOSE: Firstly, this study provides a real-time implementation of online dose reconstruction for tracked volumetric arc therapy (VMAT). Secondly, this study describes a novel offline quality assurance tool, based on commercial dose calculation algorithms. METHODS: Online dose reconstruction for VMAT is a computationally challenging task in terms of computer memory usage and calculation speed. To potentially reduce the amount of memory used, we analyzed the impact of beam angle sampling for dose calculation on the accuracy of the dose distribution. To establish the performance of the method, we planned two single-arc VMAT prostate stereotactic body radiation therapy cases for delivery with dynamic MLC tracking. For quality assurance of our online dose reconstruction method we have also developed a stand-alone offline dose reconstruction tool, which utilizes the RayStation treatment planning system to calculate dose. RESULTS: For the online reconstructed dose distributions of the tracked deliveries, we could establish strong resemblance for 72 and 36 beam co-planar equidistant beam samples with less than 1.2% deviation for the assessed dose-volume indicators (clinical target volume D98 and D2, and rectum D2). We could achieve average runtimes of 28-31 ms per reported MLC aperture for both dose computation and accumulation, meeting our real-time requirement. To cross-validate the offline tool, we have compared the planned dose to the offline reconstructed dose for static deliveries and found excellent agreement (3%/3 mm global gamma passing rates of 99.8%-100%). CONCLUSION: Being able to reconstruct dose during delivery enables online quality assurance and online replanning strategies for VMAT. The offline quality assurance tool provides the means to validate novel online dose reconstruction applications using a commercial dose calculation engine.

Towards real-time photon Monte Carlo dose calculation in the cloud.

Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.

A kernel-based dose calculation algorithm for kV photon beams with explicit handling of energy and material dependencies.

OBJECTIVE: Mimicking state-of-the-art patient radiotherapy with high-precision irradiators for small animals is expected to advance the understanding of dose-effect relationships and radiobiology in general. We work on the implementation of intensity-modulated radiotherapy-like irradiation schemes for small animals. As a first step, we present a fast analytical dose calculation algorithm for keV photon beams. METHODS: We follow a superposition-convolution approach adapted to kV X-rays, based on previous work for microbeam therapy. We assume local energy deposition at the photon interaction point due to the short electron ranges in tissue. This allows us to separate the dose calculation into locally absorbed primary dose and the scatter contribution, calculated in a point kernel approach. We validate our dose model against Geant4 Monte Carlo (MC) simulations and compare the results to Muriplan (XStrahl Ltd, Camberley, UK). RESULTS: For field sizes of (1 mm)2 to (1 cm)2 in water, the depth dose curves show a mean disagreement of 1.7% to MC simulations, with the largest deviations in the entrance region (4%) and at large depths (5% at 7 cm). Larger discrepancies are observed at water-to-bone boundaries, in bone and at the beam edges in slab phantoms and a mouse brain. Calculation times are in the order of 5 s for a single beam. CONCLUSION: The algorithm shows good agreement with MC simulations in an initial validation. It has the potential to become an alternative to full MC dose calculation. Advances in knowledge: The presented algorithm demonstrates the potential of kernel-based dose calculation for kV photon beams. It will be valuable in intensity-modulated radiotherapy and inverse treatment planning for high precision small-animal radiotherapy.

Real-time 4D dose reconstruction for tracked dynamic MLC deliveries for lung SBRT.

PURPOSE: This study provides a proof of concept for real-time 4D dose reconstruction for lung stereotactic body radiation therapy (SBRT) with multileaf collimator (MLC) tracking and assesses the impact of tumor tracking on the size of target margins. METHODS: The authors have implemented real-time 4D dose reconstruction by connecting their tracking and delivery software to an Agility MLC at an Elekta Synergy linac and to their in-house treatment planning software (TPS). Actual MLC apertures and (simulated) target positions are reported to the TPS every 40 ms. The dose is calculated in real-time from 4DCT data directly after each reported aperture by utilization of precalculated dose-influence data based on a Monte Carlo algorithm. The dose is accumulated onto the peak-exhale (reference) phase using energy-mass transfer mapping. To investigate the impact of a potentially reducible safety margin, the authors have created and delivered treatment plans designed for a conventional internal target volume (ITV) + 5 mm, a midventilation approach, and three tracking scenarios for four lung SBRT patients. For the tracking plans, a moving target volume (MTV) was established by delineating the gross target volume (GTV) on every 4DCT phase. These were rigidly aligned to the reference phase, resulting in a unified maximum GTV to which a 1, 3, or 5 mm isotropic margin was added. All scenarios were planned for 9-beam step-and-shoot IMRT to meet the criteria of RTOG 1021 (3 × 18 Gy). The GTV 3D center-of-volume shift varied from 6 to 14 mm. RESULTS: Real-time dose reconstruction at 25 Hz could be realized on a single workstation due to the highly efficient implementation of dose calculation and dose accumulation. Decreased PTV margins resulted in inadequate target coverage during untracked deliveries for patients with substantial tumor motion. MLC tracking could ensure the GTV target dose for these patients. Organ-at-risk (OAR) doses were consistently reduced by decreased PTV margins. The tracked MTV + 1 mm deliveries resulted in the following OAR dose reductions: lung V20 up to 3.5%, spinal cord D2 up to 0.9 Gy/Fx, and proximal airways D2 up to 1.4 Gy/Fx. CONCLUSIONS: The authors could show that for patient data at clinical resolution and realistic motion conditions, the delivered dose could be reconstructed in 4D for the whole lung volume in real-time. The dose distributions show that reduced margins yield lower doses to healthy tissue, whilst target dose can be maintained using dynamic MLC tracking.

Physically constrained voxel-based penalty adaptation for ultra-fast IMRT planning.

Conventional treatment planning in intensity-modulated radiation therapy (IMRT) is a trial-and-error process that usually involves tedious tweaking of optimization parameters. Here, we present an algorithm that automates part of this process, in particular the adaptation of voxel-based penalties within normal tissue. Thereby, the proposed algorithm explicitly considers a priori known physical limitations of photon irradiation. The efficacy of the developed algorithm is assessed during treatment planning studies comprising 16 prostate and 5 head and neck cases. We study the eradication of hot spots in the normal tissue, effects on target coverage and target conformity, as well as selected dose volume points for organs at risk. The potential of the proposed method to generate class solutions for the two indications is investigated. Run-times of the algorithms are reported. Physically constrained voxel-based penalty adaptation is an adequate means to automatically detect and eradicate hot-spots during IMRT planning while maintaining target coverage and conformity. Negative effects on organs at risk are comparably small and restricted to lower doses. Using physically constrained voxel-based penalty adaptation, it was possible to improve the generation of class solutions for both indications. Considering the reported run-times of less than 20 s, physically constrained voxel-based penalty adaptation has the potential to reduce the clinical workload during planning and automated treatment plan generation in the long run, facilitating adaptive radiation treatments.

Interactive dose shaping part 1: a new paradigm for IMRT treatment planning.

In this work we present a novel treatment planning technique called interactive dose shaping (IDS) to be employed for the optimization of intensity modulated radiation therapy (IMRT). IDS does not rely on a Newton-based optimization algorithm which is driven by an objective function formed of dose volume constraints on pre-segmented volumes of interest (VOIs). Our new planning technique allows for direct, interactive adaptation of localized planning features. This is realized by a dose modification and recovery (DMR) planning engine which implements a two-step approach: firstly, the desired localized plan adaptation is imposed on the current plan (modification) while secondly inevitable, undesired disturbances of the dose pattern elsewhere are compensated for automatically by the recovery module. Together with an ultra-fast dose update calculation method the DMR engine has been implemented in a newly designed 3D therapy planning system Dynaplan enabling true real-time interactive therapy planning. Here we present the underlying strategy and algorithms of the DMR based planning concept. The functionality of the IDS planning approach is demonstrated for a phantom geometry of clinical resolution and size.

Interactive dose shaping part 2: proof of concept study for six prostate patients.

Recently we introduced interactive dose shaping (IDS) as a new IMRT planning strategy. This planning concept is based on a hierarchical sequence of local dose modification and recovery operations. The purpose of this work is to provide a feasibility study for the IDS planning strategy based on a small set of six prostate patients. The IDS planning paradigm aims to perform interactive local dose adaptations of an IMRT plan without compromising already established valuable dose features in real-time. Various IDS tools were developed in our in-house treatment planning software Dynaplan and were utilized to create IMRT treatment plans for six patients with an adeno-carcinoma of the prostate. The sequenced IDS treatment plans were compared to conventionally optimized clinically approved plans (9 beams, co-planar). For each patient, several IDS plans were created, with different trade-offs between organ sparing and target coverage. The reference dose distributions were imported into Dynaplan. For each patient, the IDS treatment plan with a similar or better trade-off between target coverage and OAR sparing was selected for plan evaluation, guided by a physician. For this initial study we were able to generate treatment plans for prostate geometries in 15-45 min. Individual local dose adaptations could be performed in less than one second. The average differences compared to the reference plans were for the mean dose: 0.0 Gy (boost) and 1.2 Gy (PTV), for D98% : -1.1 Gy and for D2% : 1.1 Gy (both target volumes). The dose-volume quality indicators were well below the Quantec constraints. However, we also observed limitations of our currently implemented approach. Most prominent was an increase of the non-tumor integral dose by 16.4% on average, demonstrating that further developments of our planning strategy are required.

Fast CPU-based Monte Carlo simulation for radiotherapy dose calculation.

Monte-Carlo (MC) simulations are considered to be the most accurate method for calculating dose distributions in radiotherapy. Its clinical application, however, still is limited by the long runtimes conventional implementations of MC algorithms require to deliver sufficiently accurate results on high resolution imaging data. In order to overcome this obstacle we developed the software-package PhiMC, which is capable of computing precise dose distributions in a sub-minute time-frame by leveraging the potential of modern many- and multi-core CPU-based computers. PhiMC is based on the well verified dose planning method (DPM). We could demonstrate that PhiMC delivers dose distributions which are in excellent agreement to DPM. The multi-core implementation of PhiMC scales well between different computer architectures and achieves a speed-up of up to 37[Formula: see text] compared to the original DPM code executed on a modern system. Furthermore, we could show that our CPU-based implementation on a modern workstation is between 1.25[Formula: see text] and 1.95[Formula: see text] faster than a well-known GPU implementation of the same simulation method on a NVIDIA Tesla C2050. Since CPUs work on several hundreds of GB RAM the typical GPU memory limitation does not apply for our implementation and high resolution clinical plans can be calculated.

GPU-based high-performance computing for radiation therapy.

Recent developments in radiotherapy therapy demand high computation powers to solve challenging problems in a timely fashion in a clinical environment. The graphics processing unit (GPU), as an emerging high-performance computing platform, has been introduced to radiotherapy. It is particularly attractive due to its high computational power, small size, and low cost for facility deployment and maintenance. Over the past few years, GPU-based high-performance computing in radiotherapy has experienced rapid developments. A tremendous amount of study has been conducted, in which large acceleration factors compared with the conventional CPU platform have been observed. In this paper, we will first give a brief introduction to the GPU hardware structure and programming model. We will then review the current applications of GPU in major imaging-related and therapy-related problems encountered in radiotherapy. A comparison of GPU with other platforms will also be presented.

Performance-optimized clinical IMRT planning on modern CPUs.

Intensity modulated treatment plan optimization is a computationally expensive task. The feasibility of advanced applications in intensity modulated radiation therapy as every day treatment planning, frequent re-planning for adaptive radiation therapy and large-scale planning research severely depends on the runtime of the plan optimization implementation. Modern computational systems are built as parallel architectures to yield high performance. The use of GPUs, as one class of parallel systems, has become very popular in the field of medical physics. In contrast we utilize the multi-core central processing unit (CPU), which is the heart of every modern computer and does not have to be purchased additionally. In this work we present an ultra-fast, high precision implementation of the inverse plan optimization problem using a quasi-Newton method on pre-calculated dose influence data sets. We redefined the classical optimization algorithm to achieve a minimal runtime and high scalability on CPUs. Using the proposed methods in this work, a total plan optimization process can be carried out in only a few seconds on a low-cost CPU-based desktop computer at clinical resolution and quality. We have shown that our implementation uses the CPU hardware resources efficiently with runtimes comparable to GPU implementations, at lower costs.

Comparison of beam angle selection strategies for intracranial IMRT.

PURPOSE: Various strategies to select beneficial beam ensembles for intensity-modulated radiation therapy (IMRT) have been suggested over the years. These beam angle selection (BAS) strategies are usually evaluated against reference configurations applying equispaced coplanar beams but they are not compared to one another. Here, the authors present a meta analysis of four BAS strategies that incorporates fluence optimization (FO) into BAS by combinatorial optimization (CO) and one BAS strategy that decouples FO from BAS, i.e., spherical cluster analysis (SCA). The underlying parameters of the BAS process are investigated and the dosimetric benefits of the BAS strategies are quantified. METHODS: For three intracranial lesions in proximity to organs at risk (OARs) the authors compare treatment plans applying equispaced coplanar beam ensembles with treatment plans using five different BAS strategies, i.e., four CO techniques and SCA, to establish coplanar and noncoplanar beam ensembles. Treatment plans applying 5, 7, 9, and 11 beams are investigated. For the CO strategies the authors perform BAS runs with a 5°, 10°, 15°, and 20° angular resolution, which corresponds to a minimum of 18 coplanar and a maximum of 1400 noncoplanar candidate beams. In total 272 treatment plans with different BAS settings are generated for every patient. The quality of the treatment plans is compared based on the protection of OARs yet integral dose, target homogeneity, and target conformity are also considered. RESULTS: It is possible to reduce the average mean and maximum doses in OARs by more than 4 Gy (1 Gy) with optimized noncoplanar (coplanar) beam ensembles found with BAS by CO or SCA. For BAS including FO by CO, the individual algorithm used and the angular resolution in the space of candidate beams does not have a crucial impact on the quality of the resulting treatment plans. All CO algorithms yield similar target conformity and slightly improved target homogeneity in comparison to equispaced coplanar setups. Furthermore, optimized coplanar (noncoplanar) beam ensembles enabled more than a 6% (5%) reduction of the integral dose. For SCA, however, integral dose was increased and target conformity was decreased in comparison to equispaced coplanar setups-especially for a small number of beams. CONCLUSION: Both BAS strategies incorporating FO by CO and independent BAS strategies excluding FO provide dose savings in OARs for optimized coplanar and especially noncoplanar beam ensembles; they should not be neglected in the clinic.

Characterizing the combinatorial beam angle selection problem.

The beam angle selection (BAS) problem in intensity-modulated radiation therapy is often interpreted as a combinatorial optimization problem, i.e. finding the best combination of η beams in a discrete set of candidate beams. It is well established that the combinatorial BAS problem may be solved efficiently with metaheuristics such as simulated annealing or genetic algorithms. However, the underlying parameters of the optimization process, such as the inclusion of non-coplanar candidate beams, the angular resolution in the space of candidate beams, and the number of evaluated beam ensembles as well as the relative performance of different metaheuristics have not yet been systematically investigated. We study these open questions in a meta-analysis of four strategies for combinatorial optimization in order to provide a reference for future research related to the BAS problem in intensity-modulated radiation therapy treatment planning. We introduce a high-performance inverse planning engine for BAS. It performs a full fluence optimization for ≈3600 treatment plans per hour while handling up to 50 GB of dose influence data (≈1400 candidate beams). For three head and neck patients, we compare the relative performance of a genetic, a cross-entropy, a simulated annealing and a naive iterative algorithm. The selection of ensembles with 5, 7, 9 and 11 beams considering either only coplanar or all feasible candidate beams is studied for an angular resolution of 5°, 10°, 15° and 20° in the space of candidate beams. The impact of different convergence criteria is investigated in comparison to a fixed termination after the evaluation of 10 000 beam ensembles. In total, our simulations comprise a full fluence optimization for about 3000 000 treatment plans. All four combinatorial BAS strategies yield significant improvements of the objective function value and of the corresponding dose distributions compared to standard beam configurations with equi-spaced coplanar beams. The genetic and the cross-entropy algorithms showed faster convergence in the very beginning of the optimization but the simulated annealing algorithm eventually arrived at almost the same objective function values. These three strategies typically yield clinically equivalent treatment plans. The iterative algorithm showed the worst convergence properties. The choice of the termination criterion had a stronger influence on the performance of the simulated annealing algorithm than on the performance of the genetic and the cross-entropy algorithms. We advocate to terminate the optimization process after the evaluation of 1000 beam combinations without objective function decrease. For our simulations, this resulted in an average deviation of the objective function from the reference value after 10 000 evaluated beam ensembles of 0.5% for all metaheuristics. On average, there was only a minor improvement when increasing the angular resolution in the space of candidate beam angles from 20° to 5°. However, we observed significant improvements when considering non-coplanar candidate beams for challenging head and neck cases.

Speed optimized influence matrix processing in inverse treatment planning tools.

An optimal plan in modern treatment planning tools is found through the use of an iterative optimization algorithm, which deals with a high amount of patient-related data and number of treatment parameters to be optimized. Thus, calculating a good plan is a very time-consuming process which limits the application for patients in clinics and for research activities aiming for more accuracy. A common technique to handle the vast amount of radiation dose data is the concept of the influence matrix (DIJ), which stores the dose contribution of each bixel to the patient in the main memory of the computer. This study revealed that a bottleneck for the optimization time arises from the data transfer of the dose data between the memory and the CPU. In this note, we introduce a new method which speeds up the data transportation from stored dose data to the CPU. As an example we used the DIJ approach as is implemented in our treatment planning tool KonRad, developed at the German Cancer Research Center (DKFZ) in Heidelberg. A data cycle reordering method is proposed to take the advantage of modern memory hardware. This induces a minimal eviction policy which results in a memory behaviour exhibiting a 2.6 times faster algorithm compared to the naive implementation. Although our method is described for the DIJ approach implemented in KonRad, we believe that any other planning tool which uses a similar approach to store the dose data will also benefit from the described methods.