Alexis N.T.J. Kotte

A description of discrete vessel segments in thermal modelling of tissues

In hyperthermia treatment planning vessels with a diameter larger than 0.5 mm must be treated individually. Such vessels can be described as 3D curves with associated diameters. The temperature profile along the vessel is discretized one dimensionally. Separately the tissue is discretized three dimensionally on a regular grid of voxels. The vessel as well as the tissue are positioned in one global space. Methods are supplied to describe the tissue-vessel interaction, the shift of the blood temperature profile describing the flow of blood along the vessel and the calculation of the vessel wall temperature. The calculation of the interaction is based on tissue temperature samples and the blood temperature together with the distance between the centre of the vessel and the tissue temperature sample. An analytical expression for a vessel inside a coaxial tissue cylinder is then used for the calculation of the heat flow rate across the vessel wall. The basic test system is a vessel segment embedded inside a coaxial tissue cylinder. All the tests use this setup while the following simulation parameters are varied: position and orientation of the vessel relative to the tissue grid, vessel radius, sample density of the blood temperature and power deposition inside the tissue cylinder. The blood temperature profile is examined by calculation of the local estimate of the equilibration length. All tests show excellent agreement with the theory.

Single blind randomized Phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial

BackgroundThe treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer.Methods/DesignThe FLAME-trial (F ocal L esion A blative M icroboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described.Trial registrationThis study is registered at ClinicalTrials.gov: NCT01168479

Simultaneous multi-modality ROI delineation in clinical practice

The delineation of tumors and their surrounding organs at risk is a critical step of the treatment planning for radiation therapy. Besides computer tomography (CT), other imaging modalities are used to improve the quality of the delineations, such as magnetic resonance imaging (MRI) and positron emission tomography (PET). A practical framework is presented for using multiple datasets from different modalities during the delineation phase. The system is based on two basic principles. First, all image datasets of all available modalities are displayed in their original form (in their own coordinate system, with their own spatial resolution and voxel aspect ratio), and second, delineations can take place on all orthogonal views of each dataset and changes made to a delineation are visualized in all image sets, giving direct feedback to the delineator. The major difference between the described approach and other existing delineation tools is that instead of resampling the image sets, the delineations are transformed from one dataset to another. The transformation used for transferring the delineations is obtained by rigid normalized mutual information registration. The crucial components and the benefits of the application are presented and discussed.

Development of a regional hyperthermia treatment planning system

A flexible and fast regional hyperthermia treatment planning system for the Coaxial TEM System has been devised and is presented. Using Hounsfield Unit based thresholding and manually outlining of the tumour, a 40 cm CT data set (slice thickness 5 mm) is segmented and down scaled to a resolution of 1 cm, requiring only 30 min. The SAR model is based on the finite-difference time-domain (FDTD) method. The number of time steps to achieve numerical stability has been determined and was found to be 7000. Various optimizations of the SAR model have been applied, resulting in a relatively short computation time of 3.7 h (memory requirements 121 MB) on a Pentium III, 450 MHz standard personal computer, running GNU/Linux. The model has been validated using absolute value(Ez) measurements in a standard phantom inserted in the Coaxial TEM Applicator under different conditions and a good agreement was found. Hyperthermia treatment planning in combination with the homemade visualization tools have provided much insight in the regional hyperthermia treatment with the Coaxial TEM Applicator.A flexible and fast regional hyperthermia treatment planning system for the Coaxial TEM System has been devised and is presented. Using Hounsfield Unit based thresholding and manually outlining of the tumour, a 40cm CT data set (slice thickness 5mm) is segmented and down scaled to a resolution of 1cm, requiring only 30min. The SAR model is based on the finite-difference time-domain (FDTD) method. The number of time steps to achieve numerical stability has been determined and was found to be 7000. Various optimizations of the SAR model have been applied, resulting in a relatively short computation time of 3.7h (memory requirements 121MB) on a Pentium III, 450MHz standard personal computer, running GNU/Linux. The model has been validated using |Ez| measurements in a standard phantom inserted in the Coaxial TEM Applicator under different conditions and a good agreement was found. Hyperthermia treatment planning in combination with the homemade visualization tools have provided much insight in the regional hyperthermia treatment with the Coaxial TEM Applicator.

Influence of daily setup measurements and corrections on the estimated delivered dose during IMRT treatment of prostate cancer patients

PURPOSE To evaluate the impact of marker-based position verification, using daily imaging and an off-line correction protocol, by calculating the delivered dose to prostate, rectum and bladder. METHODS Prostate cancer patients (n=217) were treated with IMRT, receiving 35 daily fractions. Plans with five beams were optimized taking target coverage (CTV, boost) and organs-at-risk (rectum and bladder) into account. PTV margins were 8mm. Prostate position was verified daily using implanted fiducial gold markers by imaging the first segment of all the five beams on an EPID. Setup deviations were corrected off-line using an adapted shrinking-action-level protocol. The estimated delivered dose, including daily organ movements, was calculated using a version of PLATOs dose engine, enabling batch processing of large numbers of patients. The dose was calculated +/- inclusion of setup corrections, and was evaluated relative to the original static plan. The marker-based measurements were considered representative for all organs. RESULTS Daily organ movements would result in an underdosage of 2-3Gy to CTV and boost volume relative to the original plan, which was prevented by daily setup corrections. The dose to rectum and bladder was on average unchanged, but a large spread was introduced by organ movements, which was reduced by including setup corrections. CONCLUSIONS Without position verification and setup corrections, margins of 8mm would be insufficient to account for position uncertainties during IMRT of prostate cancer. With the daily off-line correction protocol, the remaining variations are accommodated adequately.

Discretizing large traceable vessels and using DE‐MRI perfusion maps yields numerical temperature contours that match the MR noninvasive measurements

The success of hyperthermia treatments is dependent on thermal dose distribution. However, the three-dimensional temperature distribution remains largely unknown. Without this knowledge, the relationship between thermal dose and outcome is noisy, and therapy cannot be optimized. Accurate computations of thermal distribution can contribute to an optimized therapy. The hyperthermia modeling group in the Department of Radiotherapy, University Medical Center Utrecht devised a Discrete Vasculature [Kotte et al., Phys. Med. Biol. 41, 865-884 (1996)] model that accounts for the presence of vessel trees in the computational domain. The vessel tree geometry is tracked using magnetic resonance (MR) angiograms to a minimum diameter between 0.6 and 1 mm. However, smaller vessels (0.2-0.6 mm) are known to account for significant heat transfer. The hyperthermia group at Duke University Medical Center has proposed using perfusion maps derived from dynamic-enhanced magnetic resonance imaging to account for the tissue perfusion heterogeneity [Craciunescu et al., Int. J. Hyperthermia 17, 221-239 (2001)]. In addition, techniques for noninvasive temperature measurements have been devised to measure temperatures in vivo [Samulski et al., Int. J. Hypertherminal, 819-829 (1992)]. In this work, a patient with high-grade sarcoma has been retrospectively modeled to determine the temperature distribution achieved during a hyperthermia treatment. Available for this model were MR depicted geometry, angiograms, perfusion maps, as necessary for accurate thermal modeling, as well as MR thermometry data for validation purposes. The vasculature assembly through modifiable potential program [Van Leeuwen et al., IEEE Trans. Biomed. Eng. 45, 596-604 (1998)] was used in order to incorporate the traceable large vessels. Temperature simulations were made using different approaches to describe perfusion. The simulated cases were the bioheat equation with constant perfusion rates per tissue type, perfusion maps alone, tracked vessel tree and perfusion maps, and generated vessel tree. The results were compared with MR thermometry data for a single patient data set, concluding that a combination between large traceable vessels and perfusion map yields the best results for this particular patient. The technique has to be repeated on several patients, first with the same type of malignancy, and after that, on patients having malignancies at other different sites.

Multiatlas-based segmentation with preregistration atlas selection

PURPOSE Automatic, atlas-based segmentation of medical images benefits from using multiple atlases, mainly in terms of robustness. However, a large disadvantage of using multiple atlases is the large computation time that is involved in registering atlas images to the target image. This paper aims to reduce the computation load of multiatlas-based segmentation by heuristically selecting atlases before registration. METHODS To be able to select atlases, pairwise registrations are performed for all atlas combinations. Based on the results of these registrations, atlases are clustered, such that each cluster contains atlas that registers well to each other. This can all be done in a preprocessing step. Then, the representatives of each cluster are registered to the target image. The quality of the result of this registration is estimated for each of the representatives and used to decide which clusters to fully register to the target image. Finally, the segmentations of the registered images are combined into a single segmentation in a label fusion procedure. RESULTS The authors perform multiatlas segmentation once with postregistration atlas selection and once with the proposed preregistration method, using a set of 182 segmented atlases of prostate cancer patients. The authors performed the full set of 182 leave-one-out experiments and in each experiment compared the result of the atlas-based segmentation procedure to the known segmentation of the atlas that was chosen as a target image. The results show that preregistration atlas selection is slightly less accurate than postregistration atlas selection, but this is not statistically significant. CONCLUSIONS Based on the results the authors conclude that the proposed method is able to reduce the number of atlases that have to be registered to the target image with 80% on average, without compromising segmentation accuracy.

Influence of Antiflatulent Dietary Advice on Intrafraction Motion for Prostate Cancer Radiotherapy

PURPOSE To evaluate the effect of an antiflatulent dietary advice on the intrafraction prostate motion in patients treated with intensity-modulated radiotherapy (IMRT) for prostate cancer. METHODS AND MATERIALS Between February 2002 and December 2009, 977 patients received five-beam IMRT for prostate cancer to a dose of 76 Gy in 35 fractions combined with fiducial markers for position verification. In July 2008, the diet, consisting of dietary guidelines to obtain regular bowel movements and to reduce intestinal gas by avoiding certain foods and air swallowing, was introduced to reduce the prostate motion. The intrafraction prostate movement was determined from the portal images of the first segment of all five beams. Clinically relevant intrafraction motion was defined as ≥50% of the fractions with an intrafraction motion outside a range of 3 mm. RESULTS A total of 739 patients were treated without the diet and 105 patients were treated with radiotherapy after introduction of the diet. The median and interquartile range of the average intrafraction motion per patient was 2.53 mm (interquartile range, 2.2-3.0) without the diet and 3.00 mm (interquartile range, 2.4-3.5) with the diet (p < .0001). The percentage of patients with clinically relevant intrafraction motion increased statistically significant from 19.1% without diet to 42.9% with a diet (odds ratio, 3.18; 95% confidence interval, 2.07-4.88; p < .0001). CONCLUSIONS The results of the present study suggest that antiflatulent dietary advice for patients undergoing IMRT for prostate cancer does not reduce the intrafraction movement of the prostate. Therefore, antiflatulent dietary advice is not recommended in clinical practice for this purpose.

Effect of translational and rotational errors on complex dose distributions with off-line and on-line position verification.

PURPOSE To investigate the influence of translational and rotational errors on prostate intensity-modulated radiotherapy (IMRT) with an integrated boost to the tumor and to evaluate the effect of the use of an on-line correction protocol. METHODS AND MATERIALS For 19 patients, who had been treated with prostate IMRT and fiducial marker-based position verification, highly inhomogeneous IMRT plans, including an integrated tumor boost, were made using varying margins (2, 4, 6, and 8 mm). The measured translational and rotational errors were used to calculate the dose using two positioning strategies: an off-line and an on-line protocol to correct the translational shifts. The estimated dose to the targets and the organs at risk was compared with the intended dose. RESULTS Residual deviations after off-line correction led to statistically significant, but very small, reductions in dose coverage. Even when a 2-mm margin was used, the average reduction in dose to 99% of the volume was 1.4 +/- 1.9 Gy for the tumor, 1.5 +/- 1.5 Gy for the prostate without seminal vesicles (boost volume), and 4.3 +/- 4.6 Gy, including the seminal vesicles (clinical target volume). Patients with large systematic rotational errors demonstrated a substantial decrease in dose, especially for the clinical target volume. If an on-line correction protocol was used, the average mean dose and dose to 99% of the volume of the targets improved. However, the extensive dose reduction for patients with large rotational errors barely recovered with on-line correction. CONCLUSION For complex prostate IMRT with an integrated tumor boost, the use of an on-line correction protocol yields little improvement without the correction of rotational errors.

First patients treated with a 1.5 T MRI-Linac : Clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.