Cervix Motion in 50 Cervical Cancer Patients Assessed by Daily Cone Beam Computed Tomographic Imaging of a New Type of Marker.

PURPOSE: To evaluate a new type of marker and a new method of marker implantation and to assess interfraction cervix motion for a large population of patients with locally advanced cervical cancer by daily cone beam computed tomographic (CBCT) imaging. METHODS AND MATERIALS: We investigated the position of markers in 50 patients treated in prone position during at least 23 fractions. To reduce streaking artifacts in the planning CT scan, a new type of polymeric marker was used and compared with conventional gold markers. In addition, a new method of implantation was used in an attempt to reduce marker loss. In each fraction, a CT scan was acquired before dose delivery and aligned to the bony anatomy of the planning CT scan, simulating the clinical setup protocol. First, sufficient visibility of the markers was verified. Then, systematic and random displacement of the marker centroids was recorded and analyzed in 3 directions with regard to the planning CT and the first CBCT (to evaluate the presence of a vaginal catheter in the planning CT). Streaking artifacts were quantified with the standard deviation of the mean squared intensity difference in a radius around the marker. RESULTS: Marker loss was minimal during treatment: in only 3 of the 50 patients 1 marker was lost. Streaking artifacts for the new markers were reduced compared with conventional gold markers. For the planning CT, M/Σ/σ were 0.4/3.4/2.2 mm, 1.0/5.5/4.5 mm, and -3.9/5.1/3.6 mm for the left-right, anterior-posterior, and cranial-caudal directions, respectively. With regard to the first CBCT scan, M/Σ/σ were 0.8/2.8/2.1, 0.6/4.4/4.4, and -1.3/4.5/3.6 mm. CONCLUSIONS: A new type of marker and implantation method was shown to have significantly reduced marker loss and streaking artifacts compared with gold fiducial markers. The recorded marker displacement confirms results reported in the existing literature but for a larger dataset.

Clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid motion management in locally advanced cervical cancer IMRT.

PURPOSE: To evaluate the clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid target motion management in locally advanced cervical cancer intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: Each of the 64 patients had four markers implanted in the vaginal fornix to verify the position of the cervix during treatment. Full and empty bladder computed tomography (CT) scans were acquired prior to treatment to build a bladder volume-dependent cervix-uterus motion model for establishment of the plan library. In the first phase of clinical implementation, the library consisted of one IMRT plan based on a single model-predicted internal target volume (mpITV), covering the target for the whole pretreatment observed bladder volume range, and a 3D conformal radiation therapy (3DCRT) motion-robust backup plan based on the same mpITV. The planning target volume (PTV) combined the ITV and nodal clinical target volume (CTV), expanded with a 1-cm margin. In the second phase, for patients showing >2.5-cm bladder-induced cervix-uterus motion during planning, two IMRT plans were constructed, based on mpITVs for empty-to-half-full and half-full-to-full bladder. In both phases, a daily cone beam CT (CBCT) scan was acquired to first position the patient based on bony anatomy and nodal targets and then select the appropriate plan. Daily post-treatment CBCT was used to verify plan selection. RESULTS: Twenty-four and 40 patients were included in the first and second phase, respectively. In the second phase, 11 patients had two IMRT plans. Overall, an IMRT plan was used in 82.4% of fractions. The main reasons for selecting the motion-robust backup plan were uterus outside the PTV (27.5%) and markers outside their margin (21.3%). In patients with two IMRT plans, the half-full-to-full bladder plan was selected on average in 45% of the first 12 fractions, which was reduced to 35% in the last treatment fractions. CONCLUSIONS: The implemented online adaptive plan-of-the-day protocol for locally advanced cervical cancer enables (almost) daily tissue-sparing IMRT.

Statistical modeling of CTV motion and deformation for IMRT of early-stage rectal cancer.

PURPOSE: To derive and validate a statistical model of motion and deformation for the clinical target volume (CTV) of early-stage rectal cancer patients. METHODS AND MATERIALS: For 16 patients, 4 to 5 magnetic resonance images (MRI) were acquired before each fraction was administered. The CTV was delineated on each MRI. Using a leave-one-out methodology, we constructed a population-based principal component analysis (PCA) model of the CTV motion and deformation of 15 patients, and we tested the model on the left-out patient. The modeling error was calculated as the amount of the CTV motion-deformation of the left-out-patient that could not be explained by the PCA model. Next, the PCA model was used to construct a PCA target volume (PCA-TV) by accumulating motion-deformations simulated by the model. A PCA planning target volume (PTV) was generated by expanding the PCA-TV by uniform margins. The PCA-PTV was compared with uniform and nonuniform CTV-to-PTV margins. To allow comparison, geometric margins were determined to ensure adequate coverage, and the volume difference between the PTV and the daily CTV (CTV-to-PTV volume) was calculated. RESULTS: The modeling error ranged from 0.9 ± 0.5 to 2.9 ± 2.1 mm, corresponding to a reduction of the CTV motion-deformation between 6% and 60% (average, 23% ± 11%). The reduction correlated with the magnitude of the CTV motion-deformation (P<.001, R=0.66). The PCA-TV and the CTV required 2-mm and 7-mm uniform margins, respectively. The nonuniform CTV-to-PTV margins were 4 mm in the left, right, inferior, superior, and posterior directions and 8 mm in the anterior direction. Compared to uniform and nonuniform CTV-to-PTV margins, the PCA-based PTV significantly decreased (P<.001) the average CTV-to-PTV volume by 128 ± 20 mL (49% ± 4%) and by 35 ± 6 mL (20% ± 3.5%), respectively. CONCLUSIONS: The CTV motion-deformation of a new patient can be explained by a population-based PCA model. A PCA model-generated PTV significantly improved sparing of organs at risk compared to uniform and nonuniform CTV-to-PTV margins.

Repeat CT-scan assessment of lymph node motion in locally advanced cervical cancer patients.

PURPOSE: In cervical cancer patients the nodal clinical target volume (CTV, defined using the major pelvic blood vessels and enlarged lymph nodes) is assumed to move synchronously with the bony anatomy. The aim of this study was to verify this assumption by investigating the motion of the major pelvic blood vessels and enlarged lymph nodes visible in CT scans. METHODS AND MATERIALS: For 13 patients treated in prone position, four variable bladder-filling CT scans per patient, acquired at planning and after 40 Gy, were selected from an available dataset of 9-10 CT scans. The bladder, rectum, and the nodal-vessels structure containing the iliac vessels and all visible enlarged nodes were delineated in each selected CT scan. Two online patient setup correction protocols were simulated. The first corrected bony anatomy translations and the second corrected translations and rotations. The efficacy of each correction was calculated as the overlap between the nodal-vessels structure in the reference and repeat CT scans. The motion magnitude between delineated structures was quantified using nonrigid registration. RESULTS: Translational corrections resulted in an average overlap of 58 ± 13% and in a range of motion between 9.9 and 27.3 mm. Translational and rotational corrections significantly improved the overlap (64 ± 13%, p value = 0.007) and moderately reduced the range of motion to 7.6-23.8 mm (p value = 0.03). Bladder filling changes significantly correlated with the nodal-vessels motion (p < 0.001). CONCLUSION: The motion of the nodal-vessels was large, nonrigid, patient-specific, and only moderately synchronous with the bony anatomy. This study highlights the need for caution when reducing the CTV-to-PTV (PTV planning target volume) margin of the nodal CTV for highly conformal radiation techniques.

Coupling between inter-helical hydrogen bonding and water dynamics in a proton transporter.

Long-distance proton transfers by proton pumps occurs in discrete steps that may involve the direct participation of protein sidechains and water molecules, and coupling of protonation changes to structural rearrangements of the protein matrix. Here we explore the role of inter-helical hydrogen bonding in long-distance protein conformational coupling and dynamics of internal water molecules. From molecular dynamics simulations of wild type and nine different bacteriorhodopsin mutants we find that both intra- and inter-helical hydrogen bonds are important determinants of the local protein structure, dynamics, and water interactions. Based on molecular dynamics and bioinformatics analyses, we identify an aspartate/threonine inter-helical hydrogen-bonding motif involved in controlling the local conformational dynamics. Perturbation of inter-helical hydrogen bonds can couple to rapid changes in water dynamics.

A margin-of-the-day online adaptive intensity-modulated radiotherapy strategy for cervical cancer provides superior treatment accuracy compared to clinically recommended margins: a dosimetric evaluation.

PURPOSE: To dosimetrically evaluate a margin-of-the-day (MoD) online adaptive intensity-modulated radiotherapy (IMRT) strategy for cervical cancer patients. The strategy is based on a single planning computed tomography (CT) scan and a pretreatment constructed IMRT plan library with incremental clinical target volumes (CTV)-to-planning target volumes (PTV) margins. MATERIAL AND METHODS: For 14 patients, 9-10 variable bladder filling CT scans acquired at pretreatment and after 40 Gy were available. Bladder volume variability during the treatment course was recorded by twice-weekly US bladder-volume measurements. A MoD strategy that selects the best IMRT plan of the day from a library of plans with incremental margins in steps of 5 mm was compared with a clinically recommended population-based margin (15 mm). To compare the strategies, for each fraction that had a recorded US bladder-volume measurement, the CT scan with the nearest bladder volume was selected from the pretreatment CT series and from the CT series acquired after 40 Gy. A frequency-weighted average of the dose-volume histograms (DVH) parameters calculated for the two selected CT scans was used to estimate the DVH parameters of the fraction of interest. RESULTS: The 15-mm recommended margin resulted in cervix-uterus underdosage in six of 14 patients. Compared with the 15-mm margin, the MoD strategy resulted in significantly better cervix-uterus coverage (p = 0.008) without a significant difference in the sparing of rectum, bladder, and small bowel. For each patient, 3-8 (median 5) plans were needed in the library of plans for the MoD strategy. The required range of the MoD was 5-45 mm (median 15 mm). Twenty-five percent of all fractions could be treated with a MoD of 5 mm and 81% of all fractions could be treated with a MoD up to 25 mm. CONCLUSIONS: Compared with a clinically recommended margin, a simple online adaptive strategy resulted in better cervix-uterus coverage without compromising organs at risk sparing.

Toward an individualized target motion management for IMRT of cervical cancer based on model-predicted cervix-uterus shape and position.

BACKGROUND AND PURPOSE: To design and evaluate a 3D patient-specific model to predict the cervix-uterus shape and position. METHODS AND MATERIALS: For 13 patients lying in prone position, 10 variable bladder filling CT-scans were acquired, 5 at planning and 5 after 40Gy. The delineated cervix-uterus volumes in 2-5 pre-treatment CT-scans were used to generate patient-specific models that predict the cervix-uterus geometry by bladder volume. Model predictions were compared to delineations, excluding those used for model construction. The prediction error was quantified by the margin required around the predicted volumes to accommodate 95% of the delineated volume and by the predicted-to-delineated surface distance. RESULTS: The prediction margin was significantly smaller (average 50%) than the margin encompassing the cervix-uterus motion. The prediction margin could be decreased (from 7 to 5mm at planning and from 10 to 8mm after 40Gy) by increasing (from 2 to 5) the number of CT-scans used for the model construction. CONCLUSION: For most patients, even with a model based on only two CT-scans, the prediction error was well below the margin encompassing the cervix-uterus motion. The described approach could be used to create prior to treatment, an individualized treatment strategy.

Three-dimensional dose addition of external beam radiotherapy and brachytherapy for oropharyngeal patients using nonrigid registration.

PURPOSE: To develop and evaluate a method for adding dose distributions of combined external beam radiotherapy (EBRT) and brachytherapy (BT) for oropharyngeal patients. METHODS AND MATERIALS: Two computed tomography (CT) scans were used for 5 patients: the EBRT CT, used for EBRT planning, and the BT CT, acquired after catheter implantation. For each scan, the salivary glands and the chewing and swallowing muscles were contoured, and a dose distribution was calculated. A nonrigid transformation was obtained by registering the organs' surfaces. Then the BT dose distribution was mapped onto the EBRT dose distribution by applying the transformation obtained. To account for differences in fractionation, the physical doses were converted to equivalent dose in 2 Gy (EQD(2)), and the total dose was found by adding dose voxel by voxel. The robustness of the dose addition was investigated by varying delineations and input parameters of the registration method and by varying the α/ß parameter for EQD(2). The effect of the perturbations was quantified using dose-volume histograms (DVH) and gamma analyses (distance-to-agreement/dose-difference = 1 mm/1 Gy). RESULTS: The variations in input parameters and delineations caused only small perturbations in the DVH of the added dose distributions. For most organs the gamma index was low, and it was moderately elevated for organs lying in areas with a steep gradient (median gamma index ≤ 2.3 for constrictor muscles, ≤ 0.7 for all other organs). CONCLUSIONS: The presented method allows adding dose distributions of combined EBRT and BT for oropharyngeal patients. In general, the method is reliable and robust with respect to uncertainties in organ delineation, perturbations in input parameters of the method, and α/ß values.

A symmetric nonrigid registration method to handle large organ deformations in cervical cancer patients.

PURPOSE: Modern radiotherapy requires assessment of patient anatomical changes. By using unidirectional registration methods, the quantified anatomical changes are asymmetric, i.e., depend on the direction of the registration. Moreover, the registration is challenged by the large and complex organ deformations that can occur in, e.g., cervical cancer patients. The aim of this work was to develop, test, and validate a symmetric feature-based nonrigid registration method that can handle organs with large-scale deformations. METHODS: A symmetric version of the unidirectional thin plate spline robust point matching (TPS-RPM) algorithm was developed, implemented, tested, and validated. Tests were performed by using the delineated cervix and uterus and bladder in CT scans of five cervical cancer patients. For each patient, five CT scans with a large variability in organ shape, volume, and deformations were acquired. Both the symmetric and the unidirectional algorithm were employed to calculate the registration geometric accuracy (surface distance and surface coverage errors), the inverse consistency, the residual distances after transforming anatomical landmarks, and the registration time. Additionally, to facilitate the further use of our symmetric method, a large set of input parameters was tested. RESULTS: The developed symmetric algorithm handled successfully the registration of bladders with extreme volume change for which TPS-RPM failed. Compared to the unidirectional algorithm the symmetric algorithm improved, for the registration of organs with large volume change, the inverse consistency by 78% and the surface coverage by 46%. Similarly, for organs with small volume change, the symmetric algorithm improved the inverse consistency by 69% and the surface coverage by 13%. The method allowed for anatomically coherent registration in only 35 s for cervix-uterus and 151 s for bladder, while keeping the inverse consistency errors around 1 mm and the surface matching errors below 1 mm. Compared to rigid alignment the symmetric method reduced the residual distances between anatomical landmarks from a range of 5.8 +/- 2-70.1 +/- 20.1 mm to a range of 1.9 +/- 0.2-8.5 +/- 5.2 mm. CONCLUSIONS: The developed symmetric method could be employed to perform fast, accurate, consistent, and anatomically coherent registration of organs with large and complex deformations. Therefore, the method is a useful tool that could support further developments in high precision image guided radiotherapy.

A novel flexible framework with automatic feature correspondence optimization for nonrigid registration in radiotherapy.

Technical improvements in planning and dose delivery and in verification of patient positioning have substantially widened the therapeutic window for radiation treatment of cancer. However, changes in patient anatomy during the treatment limit the exploitation of these new techniques. To further improve radiation treatments, anatomical changes need to be modeled and accounted for Nonrigid registration can be used for this purpose. This article describes the design, the implementation, and the validation of a new framework for nonrigid registration for radiotherapy applications. The core of this framework is an improved version of the thin plate spline robust point matching (TPS-RPM) algorithm. The TPS-RPM algorithm estimates a global correspondence and a transformation between the points that represent organs of interest belonging to two image sets. However, the algorithm does not allow for the inclusion of prior knowledge on the correspondence of subset of points, and therefore, it can lead to inconsistent anatomical solutions. In this article TPS-RPM was improved by employing a novel correspondence filter that supports simultaneous registration of multiple structures. The improved method allows for coherent organ registration and for the inclusion of user-defined landmarks, lines, and surfaces inside and outside of structures of interest. A procedure to generate control points from segmented organs is described. The framework parameters r and lambda, which control the number of points and the nonrigidness of the transformation, respectively, were optimized for three sites with different degrees of deformation (head and neck, prostate, and cervix) using two cases per site. For the head and neck cases, the salivary glands were manually contoured on CT scans, for the prostate cases the prostate and the vesicles, and for the cervix cases the cervix uterus, the bladder, and the rectum. The transformation error obtained using the best set of parameters was below 1 mm for all the studied cases. The lengths of the deformation vectors were on average (+/- 1 standard deviation) 5.8 +/- 2.5 and 2.6 +/- 1.1 mm for the head and neck cases, 7.2 +/- 4.5 and 8.6 +/- 1.9 mm for the prostate cases, and 19.0 +/- 11.6 and 14.5 +/- 9.3 mm for the cervix cases. Distinguishable anatomical features were identified for each case and were used to validate the registration by calculating residual distances after transformation: 1.5 +/- 0.8, 2.3 +/- 1.0, and 6.3 +/- 2.9 mm for the head and neck, prostate, and cervix sites, respectively. Finally, the authors demonstrated how the inclusion of these anatomical features in the registration process reduced the residual distances to 0.8 +/- 0.5, 0.6 +/- 0.5, and 1.3 +/- 0.7 mm for the head and neck, prostate, and cervix sites, respectively. The inclusion of additional anatomical features produced more anatomically coherent transformations without compromising the transformation error. The authors concluded that the presented nonrigid registration framework is a powerful tool to simultaneously register multiple segmented organs with very different complexities.