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1.  A novel approach for establishing benchmark CBCT/CT deformable image registrations in prostate cancer radiotherapy 
Physics in medicine and biology  2013;58(22):8077-8097.
Deformable image registration (DIR) is an integral component for adaptive radiation therapy. However, accurate registration between daily cone-beam computed tomography (CBCT) and treatment planning CT is challenging, due to significant daily variations in rectal and bladder fillings as well as the increased noise levels in CBCT images. Another significant challenge is the lack of “ground-truth” registrations in the clinical setting, which is necessary for quantitative evaluation of various registration algorithms. The aim of this study is to establish benchmark registrations of clinical patient data.
Three pairs of CT/CBCT datasets were chosen for this IRB-approved retrospective study. On each image, in order to reduce the contouring uncertainty, ten independent sets of organs were manually delineated by five physicians. The mean contour set for each image was derived from the ten contours. A set of distinctive points (round natural calcifications and 3 implanted prostate fiducial markers) were also manually identified. The mean contours and point features were then incorporated as constraints into a B-spline based DIR algorithm. Further, a rigidity penalty was imposed on the femurs and pelvic bones to preserve their rigidity. A piecewise-rigid registration approach was adapted to account for the differences in femur pose and the sliding motion between bones. For each registration, the magnitude of the spatial Jacobian (|JAC|) was calculated to quantify the tissue compression and expansion. Deformation grids and finite-element-model-based unbalanced energy maps were also reviewed visually to evaluate the physical soundness of the resultant deformations. Organ DICE indices (indicating the degree of overlap between registered organs) and residual misalignments of the fiducial landmarks were quantified.
Manual organ delineation on CBCT images varied significantly among physicians with overall mean DICE index of only 0.7 among redundant contours. Seminal vesicle contours were found to have the lowest correlation amongst physicians (DICE=0.5). After DIR, the organ surfaces between CBCT and planning CT were in good alignment with mean DICE indices of 0.9 for prostate, rectum, and bladder, and 0.8 for seminal vesicles. The Jacobian magnitudes |JAC| in the prostate, rectum, and seminal vesicles were in the range of 0.4–1.5, indicating mild compression/expansion. The bladder volume differences were larger between CBCT and CT images with mean |JAC| values of 2.2, 0.7, and 1.0 for three respective patients. Bone deformation was negligible (|JAC|=~1.0). The difference between corresponding landmark points between CBCT and CT was less than 1.0 mm after DIR.
We have presented a novel method of establishing benchmark deformable image registration accuracy between CT and CBCT images in the pelvic region. The method incorporates manually delineated organ surfaces and landmark points as well as pixel similarity in the optimization, while ensuring bone rigidity and avoiding excessive deformation in soft tissue organs. Redundant contouring is necessary to reduce the overall registration uncertainty.
PMCID: PMC4090712  PMID: 24171908
deformable image registration; finite element method; adaptive radiation therapy
2.  Performance validation of deformable image registration in the pelvic region 
Journal of Radiation Research  2013;54(Suppl 1):i120-i128.
Patients undergoing radiotherapy will inevitably show anatomical changes during the course of treatment. These can be weight loss, tumour shrinkage, and organ motion or filling changes. For advanced and adaptive radiotherapy (ART) information about anatomical changes must be extracted from repeated images in order to be able to evaluate and manage these changes. Deformable image registration (DIR) is a tool that can be used to efficiently gather information about anatomical changes. The aim of the present study was to evaluate the performance of two DIR methods for automatic organ at risk (OAR) contour propagation. Datasets from ten gynaecological patients having repeated computed tomography (CT) and cone beam computed tomography (CBCT) scans were collected. Contours were delineated on the planning CT and on every repeated scan by an expert clinician. DIR using our in-house developed featurelet-based method and the iPlan® BrainLab treatment planning system software was performed with the planning CT as reference and a selection of repeated scans as the target dataset. The planning CT contours were deformed using the resulting deformation fields and compared to the manually defined contours. Dice's similarity coefficients (DSCs) were calculated for each fractional patient scan structure, comparing the volume overlap using DIR with that using rigid registration only. No significant improvement in volume overlap was found after DIR as compared with rigid registration, independent of which image modality or DIR method was used. DIR needs to be further improved in order to facilitate contour propagation in the pelvic region in ART approaches.
PMCID: PMC3700513  PMID: 23824115
radiotherapy; registration; deformable; organ; adaptive radiotherapy
3.  A framework for deformable image registration validation in radiotherapy clinical applications 
Quantitative validation of deformable image registration (DIR) algorithms is extremely difficult because of the complexity involved in constructing a deformable phantom that can duplicate various clinical scenarios. The purpose of this study is to describe a framework to test the accuracy of DIR based on computational modeling and evaluating using inverse consistency and other methods. Three clinically relevant organ deformations were created in prostate (distended rectum and rectal gas), head and neck (large neck flexion), and lung (inhale and exhale lung volumes with variable contrast enhancement) study sets. DIR was performed using both B-spline and diffeomorphic demons algorithms in the forward and inverse direction. A compositive accumulation of forward and inverse deformation vector fields was done to quantify the inverse consistency error (ICE). The anatomical correspondence of tumor and organs at risk was quantified by comparing the original RT structures with those obtained after DIR. Further, the physical characteristics of the deformation field, namely the Jacobian and harmonic energy, were computed to quantify the preservation of image topology and regularity of spatial transformation obtained in DIR. The ICE was comparable in prostate case but the B-spline algorithm had significantly better anatomical correspondence for rectum and prostate than diffeomorphic demons algorithm. The ICE was 6.5 mm for demons algorithm for head and neck case when compared to 0.7 mm for B-spline. Since the induced neck flexion was large, the average Dice similarity coefficient between both algorithms was only 0.87, 0.52, 0.81, and 0.67 for tumor, cord, parotids, and mandible, respectively. The B-spline algorithm accurately estimated deformations between images with variable contrast in our lung study, while diffeomorphic demons algorithm led to gross errors on structures affected by contrast variation. The proposed framework offers the application of known deformations on any image datasets, to evaluate the overall accuracy and limitations of a DIR algorithm used in radiation oncology. The evaluation based on anatomical correspondence, physical characteristics of deformation field, and image characteristics can facilitate DIR verification with the ultimate goal of implementing adaptive radiotherapy. The suitability of application of a particular evaluation metric in validating DIR is dependent on the clinical deformation observed.
PMCID: PMC3732001  PMID: 23318394
deformable image registration; deformation vector field; inverse consistency error; quality assurance; adaptive radiotherapy; image-guided radiation therapy
4.  A Voxel-by-Voxel Comparison of Deformable Vector Fields Obtained by Three Deformable Image Registration Algorithms Applied to 4DCT Lung Studies 
Background: Commonly used methods of assessing the accuracy of deformable image registration (DIR) rely on image segmentation or landmark selection. These methods are very labor intensive and thus limited to relatively small number of image pairs. The direct voxel-by-voxel comparison can be automated to examine fluctuations in DIR quality on a long series of image pairs.
Methods: A voxel-by-voxel comparison of three DIR algorithms applied to lung patients is presented. Registrations are compared by comparing volume histograms formed both with individual DIR maps and with a voxel-by-voxel subtraction of the two maps. When two DIR maps agree one concludes that both maps are interchangeable in treatment planning applications, though one cannot conclude that either one agrees with the ground truth. If two DIR maps significantly disagree one concludes that at least one of the maps deviates from the ground truth. We use the method to compare 3 DIR algorithms applied to peak inhale-peak exhale registrations of 4DFBCT data obtained from 13 patients.
Results: All three algorithms appear to be nearly equivalent when compared using DICE similarity coefficients. A comparison based on Jacobian volume histograms shows that all three algorithms measure changes in total volume of the lungs with reasonable accuracy, but show large differences in the variance of Jacobian distribution on contoured structures. Analysis of voxel-by-voxel subtraction of DIR maps shows differences between algorithms that exceed a centimeter for some registrations.
Conclusion: Deformation maps produced by DIR algorithms must be treated as mathematical approximations of physical tissue deformation that are not self-consistent and may thus be useful only in applications for which they have been specifically validated. The three algorithms tested in this work perform fairly robustly for the task of contour propagation, but produce potentially unreliable results for the task of DVH accumulation or measurement of local volume change. Performance of DIR algorithms varies significantly from one image pair to the next hence validation efforts, which are exhaustive but performed on a small number of image pairs may not reflect the performance of the same algorithm in practical clinical situations. Such efforts should be supplemented by validation based on a longer series of images of clinical quality.
PMCID: PMC4316695
deformable image registration; deformable dose addition
5.  The application of PET-CT to post-mastectomy regional radiation therapy using a deformable image registration 
To evaluate the utility of the preoperative PET-CT using deformable image registration (DIR) in the treatment of patients with locally advanced breast cancer and to find appropriate radiotherapy technique for further adequate treatment of axillary nodal area.
Sixty-five breast cancer patients who had level II, III axillary or supraclavicular lymph node metastasis on 18F-FDG PET-CT and received postoperative radiotherapy after modified radical mastectomy were enrolled. One radiation oncologist contoured normal organs (axillary vessels, clavicular head, coracoids process and humeral head) and involved lymph nodes on PET-CT and simulation CT slices. After contouring, deformable image registration of PET-CT on simulation CT was carried out. To evaluate the performance of the DIR, Dice similarity coefficient (DSC) and Center of mass (COM) were used. We created two plans, one was the historically designed three field plan and the other was the modified plan based on the location of axillary lymph node, and we compared the doses that irradiated the axillary lymph nodes.
The DSCs for axillary artery, axillary vein, clavicular head, coracoids process and humeral head were 0.43 ± 0.15, 0.39 ± 0.20, 0.85 ± 0.10, 0.72 ± 0.20 and 0.77 ± 0.20, respectively. The distances between the COMs of axillary artery, axillary vein, clavicular head, coracoids process and humeral head in simulation CT and from PET-CT were 13.0 ±7.1, 20.2 ± 11.2, 4.4 ± 6.3, 3.7 ± 6.7, and 9.5 ± 25.0 mm, respectively. In the historically designed plan, only 57.7% of level II lymph nodes received more than 95% of prescribed dose and the coverage was improved to 70.0% with the modified plan (p < 0.01). For level III lymph nodes, the volumes received more than 95% of prescribed dose were similar in both plans (96.8 % vs 97.9%, p = 0.35).
Deformable image registration of PET-CT on simulation CT was helpful in the identification of the location of the preoperatively involved axillary lymph node. Historically designed three-field plan was not adequate to treat the axillary level II lymph node area. Novel treatment technique based on the location of axillary lymph node from PET-CT using DIR can result in more adequate coverage of nodal area.
PMCID: PMC3698158  PMID: 23621896
Breast cancer; Deformable image registration (DIR); Radiotherapy; PET-CT
6.  Evaluation of Four-Dimensional Computed Tomography to Four-Dimensional Cone-Beam Computed Tomography Deformable Image Registration for Lung Cancer Adaptive Radiation Therapy 
To evaluate two deformable image registration (DIR) algorithms for the purpose of contour mapping to support image guided adaptive radiotherapy with four-dimensional cone beam computed tomography (4DCBCT).
Methods and Materials
One planning 4D fan-beam CT (4DFBCT) and 7 weekly 4DCBCT scans were acquired for 10 locally advanced non-small cell lung cancer patients. The gross tumor volume (GTV) was delineated by a physician in all 4D images. End-of-inspiration phase planning 4DFBCT was registered to the corresponding phase in weekly 4DCBCT images for day-to-day registrations. For phase-to-phase registration, the end-of-inspiration phase from each 4D image was registered to the end-of-expiration phase. Two DIR algorithms—small deformation inverse consistent linear elastic (SICLE) and Insight Toolkit diffeomorphic demons (DEMONS)—were evaluated. Physician-delineated contours were compared to the warped contours by using the Dice similarity coefficient (DSC), average symmetric distance (ASD), false positive and false negative indices. The DIR results are compared to rigid registration of tumor.
For day-to-day registrations, the mean DSC was 0.75 ± 0.09 with SICLE, 0.70 ± 0.12 with DEMONS, 0.66 ± 0.12 with rigid-tumor registration and 0.60 ± 0.14 with rigid-bone registration. Results were comparable to intra-observer variability calculated from phase-to-phase registrations as well as measured inter-observer variation for one patient. SICLE and DEMONS, when compared to rigid-bone (4.1 mm) and rigid-tumor (3.6 mm) registration, respectively reduced the ASD to 2.6 and 3.3 mm. On average, SICLE and DEMONS increased the DSC to 0.80 and 0.79 respectively, compared to rigid-tumor (0.78) registrations for 4DCBCT phase-to-phase registrations.
DIR achieved comparable accuracy to reported inter-observer delineation variability and higher accuracy than rigid-tumor registration. DIR performance varied with the algorithm and the patient.
PMCID: PMC3647023  PMID: 23462422
7.  Assessing cumulative dose distributions in combined radiotherapy for cervical cancer using deformable image registration with pre-imaging preparations 
The purpose of the study was to evaluate the feasibility of deformable image registration (DIR) in assessing cumulative dose distributions of the combination of external beam radiotherapy (EBRT) and fractionated intracavitary brachytherapy (ICBT) for cervical cancer.
Materials and methods
Three-dimensional image data sets of five consecutive patients were used. The treatment plan consisted of whole pelvic EBRT (total dose: 45 Gy in 25 fractions) combined with computed tomography (CT)-based high-dose rate ICBT (≥24 Gy in 4 fractions to the high risk clinical target volume (HR-CTV)). Organs at risk and HR-CTV were contoured on each CT images and dose-volume parameters were acquired. Pre-imaging preparations were performed prior to each ICBT to minimize the uncertainty of the organ position. Physical doses of each treatment were converted to biologically equivalent doses in 2 Gy daily fractions by the linear quadratic model. Three-dimensional dose distributions of each treatment were accumulated on CT images of the first ICBT using DIR with commercially available image registration software (MIM Maestro®). To compare with DIR, 3D dose distributions were fused by rigid registration based on bony structure matching. To evaluate the accuracy of DIR, the Dice similarity coefficient (DSC) was measured between deformed contours and initial contours.
The cumulative dose distributions were successfully illustrated on the CT images using DIR. Mean DSCs of the HR-CTV, rectum, and bladder were 0.46, 0.62 and 0.69, respectively, with rigid registration; and 0.78, 0.76, and 0.87, respectively, with DIR (p <0.05). The mean DSCs derived from our DIR procedure were comparable to those of previous reports describing the quality of DIR algorithms in the pelvic region. DVH parameters derived from the 2 methods showed no significant difference.
Our results suggest that DIR-based dose accumulation may be acceptable for assessing cumulative dose distributions to assess doses to the tumor and organs at risk in combined radiotherapy for cervical cancer under pre-imaging preparations.
PMCID: PMC4296553  PMID: 25526986
Radiotherapy; Cervical cancer; Deformable image registration
8.  Evaluation of the deformation and corresponding dosimetric implications in prostate cancer treatment 
Physics in medicine and biology  2012;57(17):10.1088/0031-9155/57/17/5361.
The cone-beam computed tomography (CBCT) imaging modality is an integral component of image-guided adaptive radiation therapy (IGART), which uses patient-specific dynamic/temporal information for potential treatment plan modification. In this study, an offline process for the integral component IGART framework has been implemented that consists of deformable image registration (DIR) and its validation, dose reconstruction, dose accumulation and dose verification. This study compares the differences between planned and estimated delivered doses under an IGART framework of five patients undergoing prostate cancer radiation therapy. The dose calculation accuracy on CBCT was verified by measurements made in a Rando pelvic phantom. The accuracy of DIR on patient image sets was evaluated in three ways: landmark matching with fiducial markers, visual image evaluation and unbalanced energy (UE); UE has been previously demonstrated to be a feasible method for the validation of DIR accuracy at a voxel level. The dose calculated on each CBCT image set was reconstructed and accumulated over all fractions to reflect the ‘actual dose’ delivered to the patient. The deformably accumulated (delivered) plans were then compared to the original (static) plans to evaluate tumor and normal tissue dose discrepancies. The results support the utility of adaptive planning, which can be used to fully elucidate the dosimetric impact based on the simulated delivered dose to achieve the desired tumor control and normal tissue sparing, which may be of particular importance in the context of hypofractionated radiotherapy regimens.
PMCID: PMC3652266  PMID: 22863976
9.  The distance discordance metric - A novel approach to quantifying spatial uncertainties in intra- and inter-patient deformable image registration 
Physics in medicine and biology  2014;59(3):733-746.
Previous methods to estimate the inherent accuracy of deformable image registration (DIR) have typically been performed relative to a known ground truth, such as tracking of anatomic landmarks or known deformations in a physical or virtual phantom. In this study, we propose a new approach to estimate the spatial geometric uncertainty of DIR using statistical sampling techniques that can be applied to the resulting deformation vector fields (DVFs) for a given registration. The proposed DIR performance metric, the distance discordance metric (DDM), is based on the variability in the distance between corresponding voxels from different images, which are co-registered to the same voxel at location (X) in an arbitrarily chosen “reference” image. The DDM value, at location (X) in the reference image, represents the mean dispersion between voxels, when these images are registered to other images in the image set. The method requires at least four registered images to estimate the uncertainty of the DIRs, both for inter-and intra-patient DIR. To validate the proposed method, we generated an image set by deforming a software phantom with known DVFs. The registration error was computed at each voxel in the “reference” phantom and then compared to DDM, inverse consistency error (ICE), and transitivity error (TE) over the entire phantom. The DDM showed a higher Pearson correlation (Rp) with the actual error (Rp ranged from 0.6 to 0.9) in comparison with ICE and TE (Rp ranged from 0.2 to 0.8). In the resulting spatial DDM map, regions with distinct intensity gradients had a lower discordance and therefore, less variability relative to regions with uniform intensity. Subsequently, we applied DDM for intra-patient DIR in an image set of 10 longitudinal computed tomography (CT) scans of one prostate cancer patient and for inter-patient DIR in an image set of 10 planning CT scans of different head and neck cancer patients. For both intra- and inter-patient DIR, the spatial DDM map showed large variation over the volume of interest (the pelvis for the prostate patient and the head for the head and neck patients). The highest discordance was observed in the soft tissues, such as the brain, bladder, and rectum, due to higher variability in the registration. The smallest DDM values were observed in the bony structures in the pelvis and the base of the skull. The proposed metric, DDM, provides a quantitative tool to evaluate the performance of DIR when a set of images is available. Therefore, DDM can be used to estimate and visualize the uncertainty of intra- and/or inter-patient DIR based on the variability of the registration rather than the absolute registration error.
PMCID: PMC3995002  PMID: 24440838
Deformable image registration; distance discordance; uncertainty; inaccuracy
10.  Accuracy of inverse treatment planning on substitute CT images derived from MR data for brain lesions 
In this pilot study we evaluated the performance of a substitute CT (s-CT) image derived from MR data of the brain, as a basis for optimization of intensity modulated rotational therapy, final dose calculation and derivation of reference images for patient positioning.
S-CT images were created using a Gaussian mixture regression model on five patients previously treated with radiotherapy. Optimizations were compared using Dmax, Dmin, Dmedian and Dmean measures for the target volume and relevant risk structures. Final dose calculations were compared using gamma index with 1%/1 mm and 3%/3 mm acceptance criteria. 3D geometric evaluation was conducted using the DICE similarity coefficient for bony structures. 2D geometric comparison of digitally reconstructed radiographs (DRRs) was performed by manual delineation of relevant structures on the s-CT DRR that were transferred to the CT DRR and compared by visual inspection.
Differences for the target volumes in optimization comparisons were small in general, e.g. a mean difference in both Dmin and Dmax within ±0.3%. For the final dose calculation gamma evaluations, 100% of the voxels passed the 1%/1 mm criterion within the PTV. Within the entire external volume between 99.4% and 100% of the voxels passed the 3%/3 mm criterion. In the 3D geometric comparison, the DICE index varied between approximately 0.8-0.9, depending on the position in the skull. In the 2D DRR comparisons, no appreciable visual differences were found.
Even though the present work involves a limited number of patients, the results provide a strong indication that optimization and dose calculation based on s-CT data is accurate regarding both geometry and dosimetry.
PMCID: PMC4299127  PMID: 25575414
Radiotherapy; Treatment planning; MRI; Substitute CT; s-CT
11.  Retrospective feasibility study of simultaneous integrated boost in cervical cancer using tomotherapy: the impact of organ motion and tumor regression 
Whole pelvis intensity modulated radiotherapy (IMRT) is increasingly being used to treat cervical cancer aiming to reduce side effects. Encouraged by this, some groups have proposed the use of simultaneous integrated boost (SIB) to target the tumor, either to get a higher tumoricidal effect or to replace brachytherapy. Nevertheless, physiological organ movement and rapid tumor regression throughout treatment might substantially reduce any benefit of this approach.
To evaluate the clinical target volume - simultaneous integrated boost (CTV-SIB) regression and motion during chemo-radiotherapy (CRT) for cervical cancer, and to monitor treatment progress dosimetrically and volumetrically to ensure treatment goals are met.
Methods and materials
Ten patients treated with standard doses of CRT and brachytherapy were retrospectively re-planned using a helical Tomotherapy - SIB technique for the hypothetical scenario of this feasibility study. Target and organs at risk (OAR) were contoured on deformable fused planning-computed tomography and megavoltage computed tomography images. The CTV-SIB volume regression was determined. The center of mass (CM) was used to evaluate the degree of motion. The Dice’s similarity coefficient (DSC) was used to assess the spatial overlap of CTV-SIBs between scans. A cumulative dose-volume histogram modeled estimated delivered doses.
The CTV-SIB relative reduction was between 31 and 70%. The mean maximum CM change was 12.5, 9, and 3 mm in the superior-inferior, antero-posterior, and right-left dimensions, respectively. The CTV-SIB-DSC approached 1 in the first week of treatment, indicating almost perfect overlap. CTV-SIB-DSC regressed linearly during therapy, and by the end of treatment was 0.5, indicating 50% discordance. Two patients received less than 95% of the prescribed dose. Much higher doses to the OAR were observed. A multiple regression analysis showed a significant interaction between CTV-SIB reduction and OAR dose increase.
The CTV-SIB had important regression and motion during CRT, receiving lower therapeutic doses than expected. The OAR had unpredictable shifts and received higher doses. The use of SIB without frequent adaptation of the treatment plan exposes cervical cancer patients to an unpredictable risk of under-dosing the target and/or overdosing adjacent critical structures. In that scenario, brachytherapy continues to be the gold standard approach.
PMCID: PMC3551799  PMID: 23286694
Cervical cancer; IMRT-tomotherapy; Simultaneous integrated boost; SIB; Organ motion
12.  Using patient-specific phantoms to evaluate deformable image registration algorithms for adaptive radiation therapy 
The quality of adaptive treatment planning depends on the accuracy of its underlying deformable image registration (DIR). The purpose of this study is to evaluate the performance of two DIR algorithms, B-spline–based deformable multipass (DMP) and deformable demons (Demons), implemented in a commercial software package. Evaluations were conducted using both computational and physical deformable phantoms. Based on a finite element method (FEM), a total of 11 computational models were developed from a set of CT images acquired from four lung and one prostate cancer patients. FEM generated displacement vector fields (DVF) were used to construct the lung and prostate image phantoms. Based on a fast-Fourier transform technique, image noise power spectrum was incorporated into the prostate image phantoms to create simulated CBCT images. The FEM-DVF served as a gold standard for verification of the two registration algorithms performed on these phantoms. The registration algorithms were also evaluated at the homologous points quantified in the CT images of a physical lung phantom. The results indicated that the mean errors of the DMP algorithm were in the range of 1.0 ~ 3.1 mm for the computational phantoms and 1.9 mm for the physical lung phantom. For the computational prostate phantoms, the corresponding mean error was 1.0–1.9 mm in the prostate, 1.9–2.4 mm in the rectum, and 1.8–2.1 mm over the entire patient body. Sinusoidal errors induced by B-spline interpolations were observed in all the displacement profiles of the DMP registrations. Regions of large displacements were observed to have more registration errors. Patient-specific FEM models have been developed to evaluate the DIR algorithms implemented in the commercial software package. It has been found that the accuracy of these algorithms is patient-dependent and related to various factors including tissue deformation magnitudes and image intensity gradients across the regions of interest. This may suggest that DIR algorithms need to be verified for each registration instance when implementing adaptive radiation therapy.
PMCID: PMC4041490  PMID: 24257278
deformable image registration; validation; finite element modeling; deformable phantom
For patients receiving liver stereotactic body radiotherapy (SBRT), abdominal compression can reduce organ motion, and daily image guidance can reduce setup error. The reproducibility of liver shape under compression may impact treatment delivery accuracy. The purpose of this study was to measure the interfractional variability in liver shape under compression, after best-fit rigid liver-to-liver registration from kilovoltage (kV) cone beam computed tomography (CBCT) scans to planning computed tomography (CT) scans and its impact on gross tumor volume (GTV) position.
Methods and Materials
Evaluable patients were treated in a Research Ethics Board–approved SBRT six-fraction study with abdominal compression. Kilovoltage CBCT scans were acquired before treatment and reconstructed as respiratory sorted CBCT scans offline. Manual rigid liver-to-liver registrations were performed from exhale-phase CBCT scans to exhale planning CT scans. Each CBCT liver was contoured, exported, and compared with the planning CT scan for spatial differences, by use of in house–developed finite-element model–based deformable registration (MORFEUS).
We evaluated 83 CBCT scans from 16 patients with 30 GTVs. The mean volume of liver that deformed by greater than 3 mm was 21.7%. Excluding 1 outlier, the maximum volume that deformed by greater than 3 mm was 36.3% in a single patient. Over all patients, the absolute maximum deformations in the left–right (LR), anterior–posterior (AP), and superior–inferior directions were 10.5 mm (SD, 2.2), 12.9 mm (SD, 3.6), and 5.6 mm (SD, 2.7), respectively. The absolute mean predicted impact of liver volume displacements on GTV by use of center of mass displacements was 0.09 mm (SD, 0.13), 0.13 mm (SD, 0.18), and 0.08 mm (SD, 0.07) in the left–right, anterior–posterior, and superior–inferior directions, respectively.
Interfraction liver deformations in patients undergoing SBRT under abdominal compression after rigid liver-to-liver registrations on respiratory sorted CBCT scans were small in most patients (<5 mm).
PMCID: PMC3037422  PMID: 20947263
Liver radiotherapy; Abdominal compression; Deformable registration
14.  Accuracy of deformable image registration for contour propagation in adaptive lung radiotherapy 
Deformable image registration (DIR) is an attractive method for automatic propagation of regions of interest (ROIs) in adaptive lung radiotherapy. This study investigates DIR for automatic contour propagation in adaptive Non Small Cell Lung Carcinoma patients.
Pre and mid-treatment fan beam 4D-kVCT scans were taken for 17 NSCLC patients. Gross tumour volumes (GTV), nodal-GTVs, lungs, esophagus and spinal cord were delineated on all kVCT scans. ROIs were propagated from pre- to mid-treatment images using three DIR algorithms. DIR-propagated ROIs were compared with physician-drawn ROIs on the mid-treatment scan using the Dice score and the mean slicewise Hausdorff distance to agreement (MSHD). A physician scored the DIR-propagated ROIs based on clinical utility.
Good agreement between the DIR-propagated and physician drawn ROIs was observed for the lungs and spinal cord. Agreement was not as good for the nodal-GTVs and esophagus, due to poor soft-tissue contrast surrounding these structures. 96% of OARs and 85% of target volumes were scored as requiring no or minor adjustments.
DIR has been shown to be a clinically useful method for automatic contour propagation in adaptive radiotherapy however thorough assessment of propagated ROIs by the treating physician is recommended.
PMCID: PMC3816595  PMID: 24139327
Deformable image registration; Adaptive radiotherapy; NSCLC; Automatic contour propagation
15.  Advanced Electrophysiologic Mapping Systems 
Executive Summary
To assess the effectiveness, cost-effectiveness, and demand in Ontario for catheter ablation of complex arrhythmias guided by advanced nonfluoroscopy mapping systems. Particular attention was paid to ablation for atrial fibrillation (AF).
Clinical Need
Tachycardia refers to a diverse group of arrhythmias characterized by heart rates that are greater than 100 beats per minute. It results from abnormal firing of electrical impulses from heart tissues or abnormal electrical pathways in the heart because of scars. Tachycardia may be asymptomatic, or it may adversely affect quality of life owing to symptoms such as palpitations, headaches, shortness of breath, weakness, dizziness, and syncope. Atrial fibrillation, the most common sustained arrhythmia, affects about 99,000 people in Ontario. It is associated with higher morbidity and mortality because of increased risk of stroke, embolism, and congestive heart failure. In atrial fibrillation, most of the abnormal arrhythmogenic foci are located inside the pulmonary veins, although the atrium may also be responsible for triggering or perpetuating atrial fibrillation. Ventricular tachycardia, often found in patients with ischemic heart disease and a history of myocardial infarction, is often life-threatening; it accounts for about 50% of sudden deaths.
Treatment of Tachycardia
The first line of treatment for tachycardia is antiarrhythmic drugs; for atrial fibrillation, anticoagulation drugs are also used to prevent stroke. For patients refractory to or unable to tolerate antiarrhythmic drugs, ablation of the arrhythmogenic heart tissues is the only option. Surgical ablation such as the Cox-Maze procedure is more invasive. Catheter ablation, involving the delivery of energy (most commonly radiofrequency) via a percutaneous catheter system guided by X-ray fluoroscopy, has been used in place of surgical ablation for many patients. However, this conventional approach in catheter ablation has not been found to be effective for the treatment of complex arrhythmias such as chronic atrial fibrillation or ventricular tachycardia. Advanced nonfluoroscopic mapping systems have been developed for guiding the ablation of these complex arrhythmias.
The Technology
Four nonfluoroscopic advanced mapping systems have been licensed by Health Canada:
CARTO EP mapping System (manufactured by Biosense Webster, CA) uses weak magnetic fields and a special mapping/ablation catheter with a magnetic sensor to locate the catheter and reconstruct a 3-dimensional geometry of the heart superimposed with colour-coded electric potential maps to guide ablation.
EnSite System (manufactured by Endocardial Solutions Inc., MN) includes a multi-electrode non-contact catheter that conducts simultaneous mapping. A processing unit uses the electrical data to computes more than 3,000 isopotential electrograms that are displayed on a reconstructed 3-dimensional geometry of the heart chamber. The navigational system, EnSite NavX, can be used separately with most mapping catheters.
The LocaLisa Intracardiac System (manufactured by Medtronics Inc, MN) is a navigational system that uses an electrical field to locate the mapping catheter. It reconstructs the location of the electrodes on the mapping catheter in 3-dimensional virtual space, thereby enabling an ablation catheter to be directed to the electrode that identifies abnormal electric potential.
Polar Constellation Advanced Mapping Catheter System (manufactured by Boston Scientific, MA) is a multielectrode basket catheter with 64 electrodes on 8 splines. Once deployed, each electrode is automatically traced. The information enables a 3-dimensional model of the basket catheter to be computed. Colour-coded activation maps are reconstructed online and displayed on a monitor. By using this catheter, a precise electrical map of the atrium can be obtained in several heartbeats.
Review Strategy
A systematic search of Cochrane, MEDLINE and EMBASE was conducted to identify studies that compared ablation guided by any of the advanced systems to fluoroscopy-guided ablation of tachycardia. English-language studies with sample sizes greater than or equal to 20 that were published between 2000 and 2005 were included. Observational studies on safety of advanced mapping systems and fluoroscopy were also included. Outcomes of interest were acute success, defined as termination of arrhythmia immediately following ablation; long-term success, defined as being arrhythmia free at follow-up; total procedure time; fluoroscopy time; radiation dose; number of radiofrequency pulses; complications; cost; and the cost-effectiveness ratio.
Quality of the individual studies was assessed using established criteria. Quality of the overall evidence was determined by applying the GRADE evaluation system. (3) Qualitative synthesis of the data was performed. Quantitative analysis using Revman 4.2 was performed when appropriate.
Quality of the Studies
Thirty-four studies met the inclusion criteria. These comprised 18 studies on CARTO (4 randomized controlled trials [RCTs] and 14 non-RCTs), 3 RCTs on EnSite NavX, 4 studies on LocaLisa Navigational System (1 RCT and 3 non-RCTs), 2 studies on EnSite and CARTO, 1 on Polar Constellation basket catheter, and 7 studies on radiation safety.
The quality of the studies ranged from moderate to low. Most of the studies had small sample sizes with selection bias, and there was no blinding of patients or care providers in any of the studies. Duration of follow-up ranged from 6 weeks to 29 months, with most having at least 6 months of follow-up. There was heterogeneity with respect to the approach to ablation, definition of success, and drug management before and after the ablation procedure.
Summary of Findings
Evidence is based on a small number of small RCTS and non-RCTS with methodological flaws.
Advanced nonfluoroscopy mapping/navigation systems provided real time 3-dimensional images with integration of anatomic and electrical potential information that enable better visualization of areas of interest for ablation
Advanced nonfluoroscopy mapping/navigation systems appear to be safe; they consistently shortened the fluoroscopy duration and radiation exposure.
Evidence suggests that nonfluoroscopy mapping and navigation systems may be used as adjuncts to rather than replacements for fluoroscopy in guiding the ablation of complex arrhythmias.
Most studies showed a nonsignificant trend toward lower overall failure rate for advanced mapping-guided ablation compared with fluoroscopy-guided mapping.
Pooled analyses of small RCTs and non-RCTs that compared fluoroscopy- with nonfluoroscopy-guided ablation of atrial fibrillation and atrial flutter showed that advanced nonfluoroscopy mapping and navigational systems:
Yielded acute success rates of 69% to 100%, not significantly different from fluoroscopy ablation.
Had overall failure rates at 3 months to 19 months of 1% to 40% (median 25%).
Resulted in a 10% relative reduction in overall failure rate for advanced mapping guided-ablation compared to fluoroscopy guided ablation for the treatment of atrial fibrillation.
Yielded added benefit over fluoroscopy in guiding the ablation of complex arrhythmia. The advanced systems were shown to reduce the arrhythmia burden and the need for antiarrhythmic drugs in patients with complex arrhythmia who had failed fluoroscopy-guided ablation
Based on predominantly observational studies, circumferential PV ablation guided by a nonfluoroscopy system was shown to do the following:
Result in freedom from atrial fibrillation (with or without antiarrhythmic drug) in 75% to 95% of patients (median 79%). This effect was maintained up to 28 months.
Result in freedom from atrial fibrillation without antiarrhythmic drugs in 47% to 95% of patients (median 63%).
Improve patient survival at 28 months after the procedure as compared with drug therapy.
Require special skills; patient outcomes are operator dependent, and there is a significant learning curve effect.
Complication rates of pulmonary vein ablation guided by an advanced mapping/navigation system ranged from 0% to 10% with a median of 6% during a follow-up period of 6 months to 29 months.
The complication rate of the study with the longest follow-up was 8%.
The most common complications of advanced catheter-guided ablation were stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, atrial flutter, congestive heart failure, and pulmonary vein stenosis. A small number of cases with fatal atrial-esophageal fistula had been reported and were attributed to the high radiofrequency energy used rather than to the advanced mapping systems.
Economic Analysis
An Ontario-based economic analysis suggests that the cumulative incremental upfront costs of catheter ablation of atrial fibrillation guided by advanced nonfluoroscopy mapping could be recouped in 4.7 years through cost avoidance arising from less need for antiarrhythmic drugs and fewer hospitalization for stroke and heart failure.
Expert Opinion
Expert consultants to the Medical Advisory Secretariat noted the following:
Nonfluoroscopy mapping is not necessary for simple ablation procedures (e.g., typical flutter). However, it is essential in the ablation of complex arrhythmias including these:
Symptomatic, drug-refractory atrial fibrillation
Arrhythmias in people who have had surgery for congenital heart disease (e.g., macro re-entrant tachycardia in people who have had surgery for congenital heart disease).
Ventricular tachycardia due to myocardial infarction
Atypical atrial flutter
Advanced mapping systems represent an enabling technology in the ablation of complex arrhythmias. The ablation of these complex cases would not have been feasible or advisable with fluoroscopy-guided ablation and, therefore, comparative studies would not be feasible or ethical in such cases.
Many of the studies included patients with relatively simple arrhythmias (e.g., typical atrial flutter and atrial ventricular nodal re-entrant tachycardia), for which the success rates using the fluoroscopy approach were extremely high and unlikely to be improved upon using nonfluoroscopic mapping.
By age 50, almost 100% of people who have had surgery for congenital heart disease will develop arrhythmia.
Some centres are under greater pressure because of expertise in complex ablation procedures for subsets of patients.
The use of advanced mapping systems requires the support of additional electrophysiologic laboratory time and nursing time.
For patients suffering from symptomatic, drug-refractory atrial fibrillation and are otherwise healthy, catheter ablation offers a treatment option that is less invasive than is open surgical ablation.
Small RCTs that may have been limited by type 2 errors showed significant reductions in fluoroscopy exposure in nonfluoroscopy-guided ablation and a trend toward lower overall failure rate that did not reach statistical significance.
Pooled analysis suggests that advanced mapping systems may reduce the overall failure rate in the ablation of atrial fibrillation.
Observational studies suggest that ablation guided by complex mapping/navigation systems is a promising treatment for complex arrhythmias such as highly symptomatic, drug-refractory atrial fibrillation for which rate control is not an option
In people with atrial fibrillation, ablation guided by advanced nonfluoroscopy mapping resulted in arrhythmia free rates of 80% or higher, reduced mortality, and better quality of life at experienced centres.
Although generally safe, serious complications such as stroke, atrial-esophageal, and pulmonary vein stenosis had been reported following ablation procedures.
Experts advised that advanced mapping systems are also required for catheter ablation of:
Hemodynamically unstable ventricular tachycardia from ischemic heart disease
Macro re-entrant atrial tachycardia after surgical correction of congenital heart disease
Atypical atrial flutter
Catheter ablation of atrial fibrillation is still evolving, and it appears that different ablative techniques may be appropriate depending on the characteristics of the patient and the atrial fibrillation.
Data from centres that perform electrophysiological mapping suggest that patients with drug-refractory atrial fibrillation may be the largest group with unmet need for advanced mapping-guided catheter ablation in Ontario.
Nonfluoroscopy mapping-guided pulmonary vein ablation for the treatment of atrial fibrillation has a significant learning effect; therefore, it is advisable for the province to establish centres of excellence to ensure a critical volume, to gain efficiency and to minimize the need for antiarrhythmic drugs after ablation and the need for future repeat ablation procedures.
PMCID: PMC3379531  PMID: 23074499
16.  A 4D IMRT planning method using deformable image registration to improve normal tissue sparing with contemporary delivery techniques 
We propose a planning method to design true 4-dimensional (4D) intensity-modulated radiotherapy (IMRT) plans, called the t4Dplan method, in which the planning target volume (PTV) of the individual phases of the 4D computed tomography (CT) and the conventional PTV receive non-uniform doses but the cumulative dose to the PTV of each phase, computed using deformable image registration (DIR), are uniform. The non-uniform dose prescription for the conventional PTV was obtained by solving linear equations that required motion-convolved 4D dose to be uniform to the PTV for the end-exhalation phase (PTV50) and by constraining maximum inhomogeneity to 20%. A plug-in code to the treatment planning system was developed to perform the IMRT optimization based on this non-uniform PTV dose prescription. The 4D dose was obtained by summing the mapped doses from individual phases of the 4D CT using DIR. This 4D dose distribution was compared with that of the internal target volume (ITV) method. The robustness of the 4D plans over the course of radiotherapy was evaluated by computing the 4D dose distributions on repeat 4D CT datasets. Three patients with lung tumors were selected to demonstrate the advantages of the t4Dplan method compared with the commonly used ITV method. The 4D dose distribution using the t4Dplan method resulted in greater normal tissue sparing (such as lung, stomach, liver and heart) than did plans designed using the ITV method. The dose volume histograms of cumulative 4D doses to the PTV50, clinical target volume, lung, spinal cord, liver, and heart on the 4D repeat CTs for the two patients were similar to those for the 4D dose at the time of original planning.
PMCID: PMC3162508  PMID: 21771333
4D CT; IMRT; treatment planning; respiratory motion; deform
17.  Volume-of-Change Cone-Beam CT for Image-Guided Surgery 
Physics in medicine and biology  2012;57(15):4969-4989.
C-arm cone-beam CT (CBCT) can provide intraoperative 3D imaging capability for surgical guidance, but workflow and radiation dose are the significant barriers to broad utilization. One main reason is that each 3D image acquisition requires a complete scan with a full radiation dose to present a completely new 3D image every time. In this paper, we propose to utilize patient-specific CT or CBCT as prior knowledge to accurately reconstruct the aspects of the region that have changed by the surgical procedure from only a sparse set of x-rays. The proposed methods consist of a 3D-2D registration between the prior volume and a sparse set of intraoperative x-rays, creating digitally reconstructed radiographs (DRR) from the registered prior volume, computing difference images by subtracting DRRs from the intraoperative x-rays, a penalized likelihood reconstruction of the volume of change (VOC) from the difference images, and finally a fusion of VOC reconstruction with the prior volume to visualize the entire surgical field. When the surgical changes are local and relatively small, the VOC reconstruction involves only a small volume size and a small number of projections, allowing less computation and lower radiation dose than is needed to reconstruct the entire surgical field. We applied this approach to sacroplasty phantom data obtained from a CBCT test bench and vertebroplasty data with a fresh cadaver acquired from a C-arm CBCT system with a flat-panel detector (FPD). The VOCs were reconstructed from varying number of images (10–66 images) and compared to the CBCT ground truth using four different metrics (mean squared error, correlation coefficient, structural similarity index, and perceptual difference model). The results show promising reconstruction quality with structural similarity to the ground truth close to 1 even when only 15–20 images were used, allowing dose reduction by the factor of 10–20.
PMCID: PMC3432954  PMID: 22801026
18.  Clinical evaluation of multi-atlas based segmentation of lymph node regions in head and neck and prostate cancer patients 
Semi-automated segmentation using deformable registration of selected atlas cases consisting of expert segmented patient images has been proposed to facilitate the delineation of lymph node regions for three-dimensional conformal and intensity-modulated radiotherapy planning of head and neck and prostate tumours. Our aim is to investigate if fusion of multiple atlases will lead to clinical workload reductions and more accurate segmentation proposals compared to the use of a single atlas segmentation, due to a more complete representation of the anatomical variations.
Atlases for lymph node regions were constructed using 11 head and neck patients and 15 prostate patients based on published recommendations for segmentations. A commercial registration software (Velocity AI) was used to create individual segmentations through deformable registration. Ten head and neck patients, and ten prostate patients, all different from the atlas patients, were randomly chosen for the study from retrospective data. Each patient was first delineated three times, (a) manually by a radiation oncologist, (b) automatically using a single atlas segmentation proposal from a chosen atlas and (c) automatically by fusing the atlas proposals from all cases in the database using the probabilistic weighting fusion algorithm. In a subsequent step a radiation oncologist corrected the segmentation proposals achieved from step (b) and (c) without using the result from method (a) as reference. The time spent for editing the segmentations was recorded separately for each method and for each individual structure. Finally, the Dice Similarity Coefficient and the volume of the structures were used to evaluate the similarity between the structures delineated with the different methods.
For the single atlas method, the time reduction compared to manual segmentation was 29% and 23% for head and neck and pelvis lymph nodes, respectively, while editing the fused atlas proposal resulted in time reductions of 49% and 34%. The average volume of the fused atlas proposals was only 74% of the manual segmentation for the head and neck cases and 82% for the prostate cases due to a blurring effect from the fusion process. After editing of the proposals the resulting volume differences were no longer statistically significant, although a slight influence by the proposals could be noticed since the average edited volume was still slightly smaller than the manual segmentation, 9% and 5%, respectively.
Segmentation based on fusion of multiple atlases reduces the time needed for delineation of lymph node regions compared to the use of a single atlas segmentation. Even though the time saving is large, the quality of the segmentation is maintained compared to manual segmentation.
PMCID: PMC3842681  PMID: 24090107
Atlas-based segmentation; Radiotherapy; Head and neck; Prostate; Delineation time; Multi-Atlas segmentation
19.  An assessment of PTV margin based on actual accumulated dose for prostate cancer radiotherapy 
Physics in medicine and biology  2013;58(21):7733-7744.
The purpose of this work is to present the results of a margin reduction study involving dosimetric and radiobiologic assessment of cumulative dose distributions, computed using an image guided adaptive radiotherapy based framework. Eight prostate cancer patients, treated with 7–9, 6 MV, intensity modulated radiation therapy (IMRT) fields, were included in this study. The workflow consists of cone beam CT (CBCT) based localization, deformable image registration of the CBCT to simulation CT image datasets (SIMCT), dose reconstruction and dose accumulation on the SIM-CT, and plan evaluation using radiobiological models. For each patient, three IMRT plans were generated with different margins applied to the CTV. The PTV margin for the original plan was 10 mm and 6 mm at the prostate/anterior rectal wall interface (10/6 mm) and was reduced to: (a) 5/3 mm, and (b) 3 mm uniformly. The average percent reductions in predicted tumor control probability (TCP) in the accumulated (actual) plans in comparison to the original plans over eight patients were 0.4%, 0.7% and 11.0% with 10/6 mm, 5/3 mm and 3 mm uniform margin respectively. The mean increase in predicted normal tissue complication probability (NTCP) for grades 2/3 rectal bleeding for the actual plans in comparison to the static plans with margins of 10/6, 5/3 and 3 mm uniformly was 3.5%, 2.8% and 2.4% respectively. For the actual dose distributions, predicted NTCP for late rectal bleeding was reduced by 3.6% on average when the margin was reduced from 10/6 mm to 5/3 mm, and further reduced by 1.0% on average when the margin was reduced to 3 mm. The average reduction in complication free tumor control probability (P+) in the actual plans in comparison to the original plans with margins of 10/6, 5/3 and 3 mm was 3.7%, 2.4% and 13.6% correspondingly. The significant reduction of TCP and P+ in the actual plan with 3 mm margin came from one outlier, where individualizing patient treatment plans through margin adaptation based on biological models, might yield higher quality treatments.
PMCID: PMC4073000  PMID: 24140847
20.  Dosimetric and geometric evaluation of the use of deformable image registration in adaptive intensity-modulated radiotherapy for head-and-neck cancer 
Journal of Radiation Research  2014;55(5):1002-1008.
The aim of this study was to carry out geometric and dosimetric evaluation of the usefulness of a deformable image registration algorithm utilized for adaptive head-and-neck intensity-modulated radiotherapy. Data consisted of seven patients, each with a planning CT (pCT), a rescanning CT (ReCT) and a cone beam CT (CBCT). The CBCT was acquired on the same day (±1 d) as the ReCT (i.e. at Fraction 17, 18, 23, 24 or 29). The ReCT served as ground truth. A deformed CT (dCT) with structures was created by deforming the pCT to the CBCT. The geometrical comparison was based on the volumes of the deformed, and the manually delineated structures on the ReCT. Likewise, the center of mass shift (CMS) and the Dice similarity coefficient were determined. The dosimetric comparison was performed by recalculating the initial treatment plan on the dCT and the ReCT. Dose–volume histogram (DVH) points and a range of conformity measures were used for the evaluation. We found a significant difference in the median volume of the dCT relative to that of the ReCT. Median CMS values were ∼2–5 mm, except for the spinal cord, where the median CMS was 8 mm. Dosimetric evaluation of target structures revealed small differences, while larger differences were observed for organs at risk. The deformed structures cannot fully replace manually delineated structures. Based on both geometrical and dosimetrical measures, there is a tendency for the dCT to overestimate the need for replanning, compared with the ReCT.
PMCID: PMC4202302  PMID: 24907340
adaptive radiotherapy; deformable image registration; head and neck
21.  On the Estimation of the Location of the Hippocampus in the Context of Hippocampal Avoidance Whole Brain Radiotherapy Treatment Planning 
We demonstrate a technique for estimating the location of the hippocampus in MRI and CT images for use in radiotherapy treatment planning, using both rigid and contour based deformable image registration. The automatically generated contours can be subsequently modified for a given patient.
By mapping the hippocampi from several patients into a template image set, a population-based average hippocampal atlas was generated. Approximate hippocampal contours can be automatically generated in a given image set by mapping this atlas onto it. The performance and accuracy of several atlases generated in different ways was tested on 10 MRI images and 7 CT images.
Results and Conclusions
Auto-contouring based on deformable registration significantly outperformed that based on rigid registration alone, with an average Dice similarity score of 0.62 (range .40–.76) for methods utilizing deformation. Comparable results were achieved in auto-contouring CT images when deformable registration was used, demonstrating that the methodology is robust with respect to imaging modality.
PMCID: PMC2797122  PMID: 19925026
Hippocampus; deformable registration; radiotherapy; WBRT; MRI
22.  Evolution of surface-based deformable image registration for adaptive radiotherapy of non-small cell lung cancer (NSCLC) 
To evaluate the performance of surface-based deformable image registration (DR) for adaptive radiotherapy of non-small cell lung cancer (NSCLC).
Based on 13 patients with locally advanced NSCLC, CT images acquired at treatment planning, midway and the end of the radio- (n = 1) or radiochemotherapy (n = 12) course were used for evaluation of DR. All CT images were manually [gross tumor volume (GTV)] and automatically [organs-at-risk (OAR) lung, spinal cord, vertebral spine, trachea, aorta, outline] segmented. Contours were transformed into 3D meshes using the Pinnacle treatment planning system and corresponding mesh points defined control points for DR with interpolation within the structures. Using these deformation maps, follow-up CT images were transformed into the planning images and compared with the original planning CT images.
A progressive tumor shrinkage was observed with median GTV volumes of 170 cm3 (range 42 cm3 - 353 cm3), 124 cm3 (19 cm3 - 325 cm3) and 100 cm3 (10 cm3 - 270 cm3) at treatment planning, mid-way and at the end of treatment. Without DR, correlation coefficients (CC) were 0.76 ± 0.11 and 0.74 ± 0.10 for comparison of the planning CT and the CT images acquired mid-way and at the end of treatment, respectively; DR significantly improved the CC to 0.88 ± 0.03 and 0.86 ± 0.05 (p = 0.001), respectively. With manual landmark registration as reference, DR reduced uncertainties on the GTV surface from 11.8 mm ± 5.1 mm to 2.9 mm ± 1.2 mm. Regarding the carina and intrapulmonary vessel bifurcations, DR reduced uncertainties by about 40% with residual errors of 4 mm to 6 mm on average. Severe deformation artefacts were observed in patients with resolving atelectasis and pleural effusion, in one patient, where the tumor was located around large bronchi and separate segmentation of the GTV and OARs was not possible, and in one patient, where no clear shrinkage but more a decay of the tumor was observed.
The surface-based DR performed accurately for the majority of the patients with locally advanced NSCLC. However, morphological response patterns were identified, where results of the surface-based DR are uncertain.
PMCID: PMC2804595  PMID: 20025753
23.  A “rolling average” multiple adaptive planning method to compensate for target volume changes in image-guided radiotherapy of prostate cancer 
For prostate cancer radiotherapy, the interfractional organ motion can have several forms: changes in position, shape, and volume. The interfractional motion can be managed through either online or offline image guidance (IG). The position changes are commonly corrected through online IG by correcting couch position at each treatment fraction, while the shape and volume changes, or target deformation, can be compensated by margins in offline adaptive planning. In this study, we proposed and evaluated a rolling-average (RA) adaptive replanning method to account for the target volume variations. A total of 448 repeated helical computed tomography (HCT) scans from 28 patients were included in the study. Both low-risk patients (LRP, CTV = prostate) and intermediate-risk patients (IRP, CTV = prostate + seminal vesicles) were simulated. The benefit of RA strategy was evaluated geometrically and compared with the standard online IG-only method and a single replanning adaptive hybrid strategy. A new geometric index, cumulative index of target volume (CITV), was used for the evaluation. Two extreme scenarios of target volume changes, Type Ascending and Descending, were simulated by sorting the CTV volumes of actual patient data in order to have a better evaluation of the methods. Modest target volume variations were observed in our patient group. The prostate volume change was -0.14 ± 0.11 cc/day (or -0.30% ± 0.26% per day). It is found that RA is superior to the online IG and hybrid techniques. However, the magnitude of improvement depends on how significantly and rapidly the target volume changes. On the issue of planning complexity, the hybrid is more complex than online IG only, requiring one offline replanning, and RA is significantly more complex, with multiple replanning. In clinical implementation of RA, the effectiveness and efficiency should be balanced. The effectiveness is dependent on the patient population. For low-risk patients, RA is beneficial if there is significant time trend in target volume during the treatment course of radiotherapy. The optimal number of fractions necessary for the internal target volume (ITV) construction is 2 for LRP and 3 for IRP for RA strategy.
PMCID: PMC3267238  PMID: 22231221
prostate cancer; adaptive radiotherapy; image-guided radiation therapy; intensity-modulated radiation therapy; margins
24.  Comparison of intensity-modulated radiotherapy planning based on manual and automatically generated contours using deformable image registration in four-dimensional computed tomography of lung cancer patients 
To evaluate the implications of differences between manually drawn contours and contours automatically generated by deformable image registration (DIR) for 4D treatment planning.
Material and Methods
In 12 lung cancer patients intensity-modulated radiotherapy (IMRT) planning was performed for both manual contours and automatically generated (“auto”) contours in mid and peak expiration of four-dimensional computed tomography scans with the manual contours in peak inspiration serving as the reference for the displacement vector fields. Manual and auto plans were analysed with respect to their coverage of the manual contours which were assumed to represent the anatomically correct volumes.
Auto contours were on average larger than manual contours by up to 9%. Objective scores, D2% and D98% of the PTV, homogeneity and conformity indices, and coverage of normal tissue structures (lungs, heart, esophagus, spinal cord) at defined dose levels were not significantly different between both plans (p=0.22–0.94). Differences were statistically insignificant for the generalized equivalent uniform dose of the PTV (p=0.19–0.94) and normal tissue complication probabilities for lung and esophagus (p=0.13–0.47). Dosimetric differences >2% or >1 Gy were more frequent in patients with auto/manual volume differences ≥10% (p=0.04).
The applied DIR algorithm produces clinically plausible auto contours in the majority of structures. At this stage clinical supervision of the auto contouring process is required and manual interventions may become necessary. Prior to routine use further investigations are required to particularly reduce imaging artifacts.
PMCID: PMC2238773  PMID: 18078719
Deformable image registration; automatic contouring; lung cancer; intensity modulated radiotherapy
25.  Accuracy of an Automatic Patient-Positioning System Based on the Correlation of Two Edge Images in Radiotherapy 
Journal of Digital Imaging  2010;24(2):322-330.
We have clinically evaluated the accuracy of an automatic patient-positioning system based on the image correlation of two edge images in radiotherapy. Ninety-six head & neck images from eight patients undergoing proton therapy were compared with a digitally reconstructed radiograph (DRR) of planning CT. Two edge images, a reference image and a test image, were extracted by applying a Canny edge detector algorithm to a DRR and a 2D X-ray image, respectively, of each patient before positioning. In a simulation using a humanoid phantom, performed to verify the effectiveness of the proposed method, no registration errors were observed for given ranges of rotation, pitch, and translation in the x, y, and z directions. For real patients, however, there were discrepancies between the automatic positioning method and manual positioning by physicians or technicians. Using edged head coronal- and sagittal-view images, the average differences in registration between these two methods for the x, y, and z directions were 0.11 cm, 0.09 cm and 0.11 cm, respectively, whereas the maximum discrepancies were 0.34 cm, 0.38 cm, and 0.50 cm, respectively. For rotation and pitch, the average registration errors were 0.95° and 1.00°, respectively, and the maximum errors were 3.6° and 2.3°, respectively. The proposed automatic patient-positioning system based on edge image comparison was relatively accurate for head and neck patients. However, image deformation during treatment may render the automatic method less accurate, since the test image many differ significantly from the reference image.
PMCID: PMC3056963  PMID: 20127267
Automated object detection; radiotherapy; digital image processing

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