Development of a virtual spacer to support the decision for the placement of an implantable rectum spacer for prostate cancer radiotherapy: Comparison of dose, toxicity and cost-effectiveness.

INTRODUCTION: Previous studies have shown that the implantable rectum spacer (IRS) is not beneficial for all patients. A virtual IRS (V-IRS) was constructed to help identify the patients for whom it is cost-effective to implant an IRS, and its viability as a tool to tailor the decision of an IRS implantation to be beneficial for the specified patient was assessed. Please watch animation: (https://www.youtube.com/watch?v=tDlagSXMKqw) MATERIALS AND METHODS: The V-IRS was tested on 16 patients: 8 with a rectal balloon implant (RBI) and 8 with a hydrogel spacer. A V-IRS was developed using 7 computed tomography (CT) scans of patients with a RBI. To examine the V-IRS, CT scans before and after the implantation of an IRS were used. IMRT plans were made based on CT scans before the IRS, after IRS and with the V-IRS, prescribing 70 Gray (Gy) to the planning target volume. Toxicity was accessed using externally validated normal tissue complication probability (NTCP) models, and the Cost-effectiveness was analyzed using a published Markov model. RESULTS: The rectum volume receiving 75Gy (V75) were improved by both the IRS and the V-IRS with on average 4.2% and 4.3% respectively. The largest NTCP reduction resulting from the IRS and the V-IRS was 4.0% and 3.9% respectively. The RBI was cost-effective for 1 out of 8 patients, and the hydrogel was effective for 2 out of 8 patients, and close to effective for a third patient. The classification accuracy of the model, regarding cost-effectiveness, was 100%. CONCLUSION: The V-IRS approach in combination with a toxicity prediction model and a cost-effectiveness analyses is a promising basis for a decision support tool for the implantation of either a hydrogel spacer or a rectum balloon implant.

Simulation of pseudo-CT images based on deformable image registration of ultrasound images: A proof of concept for transabdominal ultrasound imaging of the prostate during radiotherapy.

PURPOSE: Imaging of patient anatomy during treatment is a necessity for position verification and for adaptive radiotherapy based on daily dose recalculation. Ultrasound (US) image guided radiotherapy systems are currently available to collect US images at the simulation stage (USsim), coregistered with the simulation computed tomography (CT), and during all treatment fractions. The authors hypothesize that a deformation field derived from US-based deformable image registration can be used to create a daily pseudo-CT (CTps) image that is more representative of the patients' geometry during treatment than the CT acquired at simulation stage (CTsim). METHODS: The three prostate patients, considered to evaluate this hypothesis, had coregistered CT and US scans on various days. In particular, two patients had two US-CT datasets each and the third one had five US-CT datasets. Deformation fields were computed between pairs of US images of the same patient and then applied to the corresponding USsim scan to yield a new deformed CTps scan. The original treatment plans were used to recalculate dose distributions in the simulation, deformed and ground truth CT (CTgt) images to compare dice similarity coefficients, maximum absolute distance, and mean absolute distance on CT delineations and gamma index (γ) evaluations on both the Hounsfield units (HUs) and the dose. RESULTS: In the majority, deformation did improve the results for all three evaluation methods. The change in gamma failure for dose (γDose, 3%, 3 mm) ranged from an improvement of 11.2% in the prostate volume to a deterioration of 1.3% in the prostate and bladder. The change in gamma failure for the CT images (γCT, 50 HU, 3 mm) ranged from an improvement of 20.5% in the anus and rectum to a deterioration of 3.2% in the prostate. CONCLUSIONS: This new technique may generate CTps images that are more representative of the actual patient anatomy than the CTsim scan.

Review of ultrasound image guidance in external beam radiotherapy part II: intra-fraction motion management and novel applications.

Imaging has become an essential tool in modern radiotherapy (RT), being used to plan dose delivery prior to treatment and verify target position before and during treatment. Ultrasound (US) imaging is cost-effective in providing excellent contrast at high resolution for depicting soft tissue targets apart from those shielded by the lungs or cranium. As a result, it is increasingly used in RT setup verification for the measurement of inter-fraction motion, the subject of Part I of this review (Fontanarosa et al 2015 Phys. Med. Biol. 60 R77-114). The combination of rapid imaging and zero ionising radiation dose makes US highly suitable for estimating intra-fraction motion. The current paper (Part II of the review) covers this topic. The basic technology for US motion estimation, and its current clinical application to the prostate, is described here, along with recent developments in robust motion-estimation algorithms, and three dimensional (3D) imaging. Together, these are likely to drive an increase in the number of future clinical studies and the range of cancer sites in which US motion management is applied. Also reviewed are selections of existing and proposed novel applications of US imaging to RT. These are driven by exciting developments in structural, functional and molecular US imaging and analytical techniques such as backscatter tissue analysis, elastography, photoacoustography, contrast-specific imaging, dynamic contrast analysis, microvascular and super-resolution imaging, and targeted microbubbles. Such techniques show promise for predicting and measuring the outcome of RT, quantifying normal tissue toxicity, improving tumour definition and defining a biological target volume that describes radiation sensitive regions of the tumour. US offers easy, low cost and efficient integration of these techniques into the RT workflow. US contrast technology also has potential to be used actively to assist RT by manipulating the tumour cell environment and by improving the delivery of radiosensitising agents. Finally, US imaging offers various ways to measure dose in 3D. If technical problems can be overcome, these hold potential for wide-dissemination of cost-effective pre-treatment dose verification and in vivo dose monitoring methods. It is concluded that US imaging could eventually contribute to all aspects of the RT workflow.

Consequences of Intermodality Registration Errors for Intramodality 3D Ultrasound IGRT.

Intramodality ultrasound image-guided radiotherapy systems compare daily ultrasound to reference ultrasound images. Nevertheless, because the actual treatment planning is based on a reference computed tomography image, and not on a reference ultrasound image, their accuracy depends partially on the correct intermodality registration of the reference ultrasound and computed tomography images for treatment planning. The error propagation in daily patient positioning due to potential registration errors at the planning stage was assessed in this work. Five different scenarios were simulated involving shifts or rotations of ultrasound or computed tomography images. The consequences of several workflow procedures were tested with a phantom setup. As long as the reference ultrasound and computed tomography images are made to match, the patient will be in the correct treatment position. In an example with a phantom measurement, the accuracy of the performed manual fusion was found to be ≤2 mm. In clinical practice, manual registration of patient images is expected to be more difficult. Uncorrected mismatches will lead to a systematically incorrect final patient position because there will be no indication that there was a misregistration between the computed tomography and reference ultrasound images. In the treatment room, the fusion with the computed tomography image will not be visible and based on the ultrasound images the patient position seems correct.

Review of ultrasound image guidance in external beam radiotherapy: I. Treatment planning and inter-fraction motion management.

In modern radiotherapy, verification of the treatment to ensure the target receives the prescribed dose and normal tissues are optimally spared has become essential. Several forms of image guidance are available for this purpose. The most commonly used forms of image guidance are based on kilovolt or megavolt x-ray imaging. Image guidance can also be performed with non-harmful ultrasound (US) waves. This increasingly used technique has the potential to offer both anatomical and functional information.This review presents an overview of the historical and current use of two-dimensional and three-dimensional US imaging for treatment verification in radiotherapy. The US technology and the implementation in the radiotherapy workflow are described. The use of US guidance in the treatment planning process is discussed. The role of US technology in inter-fraction motion monitoring and management is explained, and clinical studies of applications in areas such as the pelvis, abdomen and breast are reviewed. A companion review paper (O'Shea et al 2015 Phys. Med. Biol. submitted) will extensively discuss the use of US imaging for intra-fraction motion quantification and novel applications of US technology to RT.

Critical assessment of intramodality 3D ultrasound imaging for prostate IGRT compared to fiducial markers.

PURPOSE: A quantitative 3D intramodality ultrasound (US) imaging system was verified for daily in-room prostate localization, and compared to prostate localization based on implanted fiducial markers (FMs). METHODS: Thirteen prostate patients underwent multiple US scans during treatment. A total of 376 US-scans and 817 matches were used to determine the intra- and interoperator variability. Additionally, eight other patients underwent daily prostate localization using both US and electronic portal imaging (EPI) with FMs resulting in 244 combined US-EPI scans. Scanning was performed with minimal probe pressure and a correction for the speed of sound aberration was performed. Uncertainties of both US and FM methods were assessed. User variability of the US method was assessed. RESULTS: The overall US user variability is 2.6 mm. The mean differences between US and FM are: 2.5 ± 4.0 mm (LR), 0.6 ± 4.9 mm (SI), and -2.3 ± 3.6 mm (AP). The intramodality character of this US system mitigates potential errors due to transducer pressure and speed of sound aberrations. CONCLUSIONS: The overall accuracy of US (3.0 mm) is comparable to our FM workflow (2.2 mm). Since neither US nor FM can be considered a gold standard no conclusions can be drawn on the superiority of either method. Because US imaging captures the prostate itself instead of surrogates no invasive procedure is required. It requires more effort to standardize US imaging than FM detection. Since US imaging does not involve a radiation burden, US prostate imaging offers an alternative for FM EPI positioning.

Active breathing control in combination with ultrasound imaging: a feasibility study of image guidance in stereotactic body radiation therapy of liver lesions.

PURPOSE: Accurate tumor positioning in stereotactic body radiation therapy (SBRT) of liver lesions is often hampered by motion and setup errors. We combined 3-dimensional ultrasound imaging (3DUS) and active breathing control (ABC) as an image guidance tool. METHODS AND MATERIALS: We tested 3DUS image guidance in the SBRT treatment of liver lesions for 11 patients with 88 treatment fractions. In 5 patients, 3DUS imaging was combined with ABC. The uncertainties of US scanning and US image segmentation in liver lesions were determined with and without ABC. RESULTS: In free breathing, the intraobserver variations were 1.4 mm in left-right (L-R), 1.6 mm in superior-inferior (S-I), and 1.3 mm anterior-posterior (A-P). and the interobserver variations were 1.6 mm (L-R), 2.8 mm (S-I), and 1.2 mm (A-P). The combined uncertainty of US scanning and matching (inter- and intraobserver) was 4 mm (1 SD). The combined uncertainty when ABC was used reduced by 1.7 mm in the S-I direction. For the L-R and A-P directions, no significant difference was observed. CONCLUSION: 3DUS imaging for IGRT of liver lesions is feasible, although using anatomic surrogates in the close vicinity of the lesion may be needed. ABC-based breath-hold in midventilation during 3DUS imaging can reduce the uncertainty of US-based 3D table shift correction.

On the significance of density-induced speed of sound variations on US-guided radiotherapy.

PURPOSE: To show the effect of speed of sound (SOS) aberration on ultrasound guided radiotherapy (US-gRT) as a function of implemented workflow. US systems assume that SOS is constant in human soft tissues (at a value of 1540 m∕s), while its actual nonuniform distribution produces small but systematic errors of up to a few millimeters in the positions of scanned structures. When a coregistered computerized tomography (CT) scan is available, the US image can be corrected for SOS aberration. Typically, image guided radiotherapy workflows implementing US systems only provide a CT scan at the simulation (SIM) stage. If changes occur in geometry or density distribution between SIM and treatment (TX) stage, SOS aberration can change accordingly, with a final impact on the measured position of structures which is dependent on the workflow adopted. METHODS: Four basic scenarios were considered of possible changes between SIM and TX: (1) No changes, (2) only patient position changes (rigid rotation-translation), (3) only US transducer position changes (constrained on patient's surface), and (4) patient tissues thickness changes. Different SOS aberrations may arise from the different scenarios, according to the specific US-gRT workflow used: intermodality (INTER) where TX US scans are compared to SIM CT scans; intramodality (INTRA) where TX US scans are compared to SIM US scans; and INTERc and INTRAc where all US images are corrected for SOS aberration (using density information provided by SIM CT). For an experimental proof of principle, the effect of tissues thickness change was simulated in the different workflows: a dual layered phantom was filled with layers of sunflower oil (SOS 1478 m∕s), water (SOS 1482 m∕s), and 20% saline solution (SOS 1700 m∕s). The phantom was US scanned, the layer thicknesses were increased and the US scans were repeated. The errors resulting from the different workflows were compared. RESULTS: Theoretical considerations show that workflows implementing SOS correction based on SIM-CT scan (INTERc, INTRAc) give null errors in all scenarios except when tissues thickness changes, where an error proportional to the degree of change in SOS maps between SIM and TX (ΔSOS) occurs. An uncorrected workflow such as INTER produces in all scenarios a pure SOS error, while uncorrected INTRA produces a null error for rotation-translation of the patient, a ΔSOS error for changing tissues thickness and an error proportional to the degree of SOS distribution change along the different lines of view when shifting the transducer. The dual layered phantom demonstrated experimentally that the effect of SOS change between SIM and TX is clinically nonrelevant, being less than the intrinsic resolution of imaging systems, even when a substantial change in thicknesses is applied, provided that a SIM-CT-based SOS aberration correction is applied. Noncorrected workflows produce errors up to 4 mm for INTER and to 3 mm for INTRA in the phantom test. CONCLUSIONS: A SOS correction is advantageous for all US-gRT workflows and clinical cases, where the effect of SOS change can be considered a second order effect.

Magnitude of speed of sound aberration corrections for ultrasound image guided radiotherapy for prostate and other anatomical sites.

PURPOSE: The purpose of this work is to assess the magnitude of speed of sound (SOS) aberrations in three-dimensional ultrasound (US) imaging systems in image guided radiotherapy. The discrepancy between the fixed SOS value of 1540 m∕s assumed by US systems in human soft tissues and its actual nonhomogeneous distribution in patients produces small but systematic errors of up to a few millimeters in the positions of scanned structures. METHODS: A correction, provided by a previously published density-based algorithm, was applied to a set of five prostate, five liver, and five breast cancer patients. The shifts of the centroids of target structures and the change in shape were evaluated. RESULTS: After the correction the prostate cases showed shifts up to 3.6 mm toward the US probe, which may explain largely the reported positioning discrepancies in the literature on US systems versus other imaging modalities. Liver cases showed the largest changes in volume of the organ, up to almost 9%, and shifts of the centroids up to more than 6 mm either away or toward the US probe. Breast images showed systematic small shifts of the centroids toward the US probe with a maximum magnitude of 1.3 mm. CONCLUSIONS: The applied correction in prostate and liver cancer patients shows positioning errors of several mm due to SOS aberration; the errors are smaller in breast cancer cases, but possibly becoming more important when breast tissue thickness increases.

A CT based correction method for speed of sound aberration for ultrasound based image guided radiotherapy.

PURPOSE: To introduce a correction for speed of sound (SOS) aberrations in three dimensional (3D) ultrasound (US) imaging systems for small but systematic positioning errors in image guided radiotherapy (IGRT) applications. US waves travel at different speeds in different human tissues. Conventional US-based imaging systems assume that SOS is constant in all tissues at 1540 m/s which is an accepted average value for soft tissues. This assumption leads to errors of up to a few millimeters when converting echo times into distances and is a source of systematic errors and image distortion in quantitative US imaging. METHODS: At simulation, US applications for IGRT provide a computed tomography (CT) image coregistered to a US volume. The CT scan provides the physical density which can be used in an empirical relationship with SOS. This can be used to correct for different SOS in different tissues within the patient. For each US scan line each voxel's axial dimension is rescaled according to the SOS associated to it. This SOS correction method was applied to US scans of a PMMA container filled with either water, a 20% saline water solution or sunflower oil, and the results were compared to the CT. The correction was also applied to an US quality assurance (QA) phantom containing rods with high ultrasound contrast. This phantom was scanned with US through a container filled with the same three liquids. Finally, the algorithm was applied to two clinical cases: a prostate cancer patient and a breast cancer patient. RESULTS: After the correction was applied to the phantom images, spatial registration between the bottom of the phantom in the US scan and in the CT scan was improved; the difference was reduced from a few millimeters to less than one millimeter for all three different liquids. Reference structures in the QA phantom appeared at more closely corresponding depths in the three cases after the correction, within 0.5 mm. Both clinical cases showed small shifts, up to 3 mm, in the positions of anatomical structures after correction. CONCLUSIONS: The SOS correction presented increases quantitative accuracy in US imaging which may lead to small but systematic improvements in patient positioning.

Improved immobilization using an individual head support in head and neck cancer patients.

The benefits of a patient-specific head support, developed to improve immobilization during radiotherapy, were determined in head and neck cancer patients. Cone-beam CTs were registered to the planning CT in five regions. Compared to the standard head support, the individual head support decreased the systematic and random errors of the inter- and intrafraction displacements and reduced deformations.