Variability in commercially available deformable image registration: A multi-institution analysis using virtual head and neck phantoms.

PURPOSE: The purpose of this study was to evaluate the performance of three common deformable image registration (DIR) packages across algorithms and institutions. METHODS AND MATERIALS: The Deformable Image Registration Evaluation Project (DIREP) provides ten virtual phantoms derived from computed tomography (CT) datasets of head-and-neck cancer patients over a single treatment course. Using the DIREP phantoms, DIR results from 35 institutions were submitted using either Velocity, MIM, or Eclipse. Submitted deformation vector fields (DVFs) were compared to ground-truth DVFs to calculate target registration error (TRE) for six regions of interest (ROIs). Statistical analysis was performed to determine the variability between each DIR software package and the variability of users within each algorithm. RESULTS: Overall mean TRE was 2.04 ± 0.35 mm for Velocity, 1.10 ± 0.29 mm for MIM, and 2.35 ± 0.15 mm for Eclipse. The MIM mean TRE was significantly different than both Velocity and Eclipse for all ROIs. Velocity and Eclipse mean TREs were not significantly different except for when evaluating the registration of the cord or mandible. Significant differences between institutions were found for the MIM and Velocity platforms. However, these differences could be explained by variations in Velocity DIR parameters and MIM software versions. CONCLUSIONS: Average TRE was shown to be <3 mm for all three software platforms. However, maximum errors could be larger than 2 cm indicating that care should be exercised when using DIR. While MIM performed statistically better than the other packages, all evaluated algorithms had an average TRE better than the largest voxel dimension. For the phantoms studied here, significant differences between algorithm users were minimal suggesting that the algorithm used may have more impact on DIR accuracy than the particular registration technique employed. A significant difference in TRE was discovered between MIM versions showing that DIR QA should be performed after software upgrades as recommended by TG-132.

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment. OBJECTIVES: To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor ß1 (TGF-ß1). DESIGN, SETTING, AND PARTICIPANTS: A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-ß1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model. MAIN OUTCOMES AND MEASURES: The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-ß1 levels was tested. RESULTS: Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-ß1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-ß1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects. CONCLUSIONS AND RELEVANCE: Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-ß1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-ß1-induced suppression of antitumor immunity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00265941.

Benchmarking of five commercial deformable image registration algorithms for head and neck patients.

Benchmarking is a process in which standardized tests are used to assess system performance. The data produced in the process are important for comparative purposes, particularly when considering the implementation and quality assurance of DIR algorithms. In this work, five commercial DIR algorithms (MIM, Velocity, RayStation, Pinnacle, and Eclipse) were benchmarked using a set of 10 virtual phantoms. The phantoms were previously developed based on CT data collected from real head and neck patients. Each phantom includes a start of treatment CT dataset, an end of treatment CT dataset, and the ground-truth deformation vector field (DVF) which links them together. These virtual phantoms were imported into the commercial systems and registered through a deformable process. The resulting DVFs were compared to the ground-truth DVF to determine the target registration error (TRE) at every voxel within the image set. Real treatment plans were also recalculated on each end of treatment CT dataset and the dose transferred according to both the ground-truth and test DVFs. Dosimetric changes were assessed, and TRE was correlated with changes in the DVH of individual structures. In the first part of the study, results show mean TRE on the order of 0.5 mm to 3 mm for all phan-toms and ROIs. In certain instances, however, misregistrations were encountered which produced mean and max errors up to 6.8 mm and 22 mm, respectively. In the second part of the study, dosimetric error was found to be strongly correlated with TRE in the brainstem, but weakly correlated with TRE in the spinal cord. Several interesting cases were assessed which highlight the interplay between the direction and magnitude of TRE and the dose distribution, including the slope of dosimetric gradients and the distance to critical structures. This information can be used to help clinicians better implement and test their algorithms, and also understand the strengths and weaknesses of a dose adaptive approach.

A virtual phantom library for the quantification of deformable image registration uncertainties in patients with cancers of the head and neck.

PURPOSE: Deformable image registration (DIR) is being used increasingly in various clinical applications. However, the underlying uncertainties of DIR are not well-understood and a comprehensive methodology has not been developed for assessing a range of interfraction anatomic changes during head and neck cancer radiotherapy. This study describes the development of a library of clinically relevant virtual phantoms for the purpose of aiding clinicians in the QA of DIR software. These phantoms will also be available to the community for the independent study and comparison of other DIR algorithms and processes. METHODS: Each phantom was derived from a pair of kVCT volumetric image sets. The first images were acquired of head and neck cancer patients prior to the start-of-treatment and the second were acquired near the end-of-treatment. A research algorithm was used to autosegment and deform the start-of-treatment (SOT) images according to a biomechanical model. This algorithm allowed the user to adjust the head position, mandible position, and weight loss in the neck region of the SOT images to resemble the end-of-treatment (EOT) images. A human-guided thin-plate splines algorithm was then used to iteratively apply further deformations to the images with the objective of matching the EOT anatomy as closely as possible. The deformations from each algorithm were combined into a single deformation vector field (DVF) and a simulated end-of-treatment (SEOT) image dataset was generated from that DVF. Artificial noise was added to the SEOT images and these images, along with the original SOT images, created a virtual phantom where the underlying "ground-truth" DVF is known. Images from ten patients were deformed in this fashion to create ten clinically relevant virtual phantoms. The virtual phantoms were evaluated to identify unrealistic DVFs using the normalized cross correlation (NCC) and the determinant of the Jacobian matrix. A commercial deformation algorithm was applied to the virtual phantoms to show how they may be used to generate estimates of DIR uncertainty. RESULTS: The NCC showed that the simulated phantom images had greater similarity to the actual EOT images than the images from which they were derived, supporting the clinical relevance of the synthetic deformation maps. Calculation of the Jacobian of the "ground-truth" DVFs resulted in only positive values. As an example, mean error statistics are presented for all phantoms for the brainstem, cord, mandible, left parotid, and right parotid. CONCLUSIONS: It is essential that DIR algorithms be evaluated using a range of possible clinical scenarios for each treatment site. This work introduces a library of virtual phantoms intended to resemble real cases for interfraction head and neck DIR that may be used to estimate and compare the uncertainty of any DIR algorithm.

Real-time tumor tracking in the lung using an electromagnetic tracking system.

PURPOSE: To describe the first use of the commercially available Calypso 4D Localization System in the lung. METHODS AND MATERIALS: Under an institutional review board-approved protocol and an investigational device exemption from the US Food and Drug Administration, the Calypso system was used with nonclinical methods to acquire real-time 4-dimensional lung tumor tracks for 7 lung cancer patients. The aims of the study were to investigate (1) the potential for bronchoscopic implantation; (2) the stability of smooth-surface beacon transponders (transponders) after implantation; and (3) the ability to acquire tracking information within the lung. Electromagnetic tracking was not used for any clinical decision making and could only be performed before any radiation delivery in a research setting. All motion tracks for each patient were reviewed, and values of the average displacement, amplitude of motion, period, and associated correlation to a sinusoidal model (R(2)) were tabulated for all 42 tracks. RESULTS: For all 7 patients at least 1 transponder was successfully implanted. To assist in securing the transponder at the tumor site, it was necessary to implant a secondary fiducial for most transponders owing to the transponder's smooth surface. For 3 patients, insertion into the lung proved difficult, with only 1 transponder remaining fixed during implantation. One patient developed a pneumothorax after implantation of the secondary fiducial. Once implanted, 13 of 14 transponders remained stable within the lung and were successfully tracked with the tracking system. CONCLUSIONS: Our initial experience with electromagnetic guidance within the lung demonstrates that transponder implantation and tracking is achievable though not clinically available. This research investigation proved that lung tumor motion exhibits large variations from fraction to fraction within a single patient and that improvements to both transponder and tracking system are still necessary to create a clinical daily-use system to assist with actual lung radiation therapy.

Image-guided bolus electron conformal therapy - a case study.

We report on our initial experience with daily image guidance for the treatment of a patient with a basal cell carcinoma of the nasal dorsum using bolus electron conformal therapy. We describe our approach to daily alignment using treatment machine-integrated megavoltage (MV) planar imaging in conjunction with cone beam CT (CBCT) volumetric imaging to ensure the best possible setup reproducibility. Based on MV imaging, beam aperture misalignment with the intended treatment region was as large as 0.5 cm in the coronal plane. Four of the five fractions analyzed show induced shifts when compared to digitally reconstructed radiographs (DRR), in the range of 0.2-0.5 cm. Daily inspection of CBCT images show that the bolus device can have significant tilt in any given direction by as much as 13° with respect to beam axis. In addition, we show that CBCT images reveal air gaps between bolus and skin that vary from day to day, and can potentially degrade surface dose coverage. Retrospective dose calculation on CBCT image sets shows that when daily shifts based on MV imaging are not corrected, geometrical miss of the planning target volume (PTV) can cause an underdosing as large as 14% based on DVH analysis of the dose to the 90% of the PTV volume.

A comparison of soft-tissue implanted markers and bony anatomy alignments for image-guided treatments of head-and-neck cancers.

PURPOSE: To compare the geometric alignments of soft-tissue implanted markers to the traditional bony-based alignments in head-and-neck cancers, on the basis of daily image guidance. Dosimetric impact of the two alignment techniques on target coverage is presented. METHODS AND MATERIALS: A total of 330 retrospective alignments (5 patients) were performed on daily megavoltage computed tomography (MVCT) image sets using both alignment techniques. Intermarker distances were tracked for all fractions to assess marker interfractional stability. Using a deformable image registration algorithm, target cumulative doses were calculated according to generated shifts on daily MVCT image sets. Target D95 was used as a dosimetric endpoint to evaluate each alignment technique. RESULTS: Intermarker distances overall were stable, with a standard deviation of <1.5 mm for all fractions and no observed temporal trends. Differences in shift magnitudes between both alignment techniques were found to be statistically significant, with a maximum observed difference of 8 mm in a given direction. Evaluation of technique-specific dose coverage based on D95 of target clinical target volume and planning target volume shows small differences (within +/-5%) compared with the kilovoltage CT plan. CONCLUSION: The use of daily MVCT imaging demonstrates that implanted markers in oral tongue and soft-palate cancers are stable localization surrogates. Alignments based on implanted markers generate shifts comparable overall to the traditional bony-based alignment, with no observed systematic difference in magnitude or direction. The cumulative dosimetric impact on target clinical target volume and planning target volume coverage was found to be similar, despite large observed differences in daily alignment shifts between the two techniques.

Megavoltage computed tomography image-based low-dose rate intracavitary brachytherapy planning for cervical carcinoma.

Initial results of megavoltage computed tomography (MVCT) brachytherapy treatment planning are presented, using a commercially available helical tomotherapy treatment unit and standard low dose rate (LDR) brachytherapy applicators used for treatment of cervical carcinoma. The accuracy of MVCT imaging techniques, and dosimetric accuracy of the CT based plans were tested with in-house and commercially-available phantoms. Three dimensional (3D) dose distributions were computed and compared to the two dimensional (2D) dosimetry results. Minimal doses received by the 2 cm3 of bladder and rectum receiving the highest doses (D(B2cc) and D(R2cc), respectively) were computed from dose-volume histograms and compared to the doses computed for the standard ICRU bladder and rectal reference dose points. Phantom test objects in MVCT image sets were localized with sub-millimetric accuracy, and the accuracy of the MVCT-based dose calculation was verified. Fifteen brachytherapy insertions were also analyzed. The ICRU rectal point dose did not differ significantly from D(R2cc) (p=0.749, mean difference was 24 cGy +/- 283 cGy). The ICRU bladder point dose was significantly lower than the D(B2cc) (p=0.024, mean difference was 291 cGy +/- 444 cGy). The median volumes of bladder and rectum receiving at least the corresponding ICRU reference point dose were 6.1 cm(3) and 2.0 cm(3), respectively. Our initial experience in using MVCT imaging for clinical LDR gynecological brachytherapy indicates that the MVCT images are of sufficient quality for use in 3D, MVCT-based dose planning.

Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.

BACKGROUND AND PURPOSE: To assess and evaluate geometrical changes in parotid glands using deformable image registration and megavoltage CT (MVCT) images. METHODS: A deformable registration algorithm was applied to 330 daily MVCT images (10 patients) to create deformed parotid contours. The accuracy and robustness of the algorithm was evaluated through visual review, comparison with manual contours, and precision analysis. Temporal changes in the parotid gland geometry were observed. RESULTS: The deformed parotid contours were qualitatively judged to be acceptable. Compared with manual contours, the uncertainties of automatically deformed contours were similar with regard to geometry and dosimetric endpoint. The day-to-day variations (1 standard deviation of errors) in the center-of-mass distance and volume were 1.61mm and 4.36%, respectively. The volumes tended to decrease with a median total loss of 21.3% (6.7-31.5%) and a median change rate of 0.7%/day (0.4-1.3%/day). Parotids migrated toward the patient center with a median total distance change of -5.26mm (0.00 to -16.35mm) and a median change rate of -0.22mm/day (0.02 to -0.56mm/day). CONCLUSION: The deformable image registration and daily MVCT images provide an efficient and reliable assessment of parotid changes over the course of a radiation therapy.

Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.

PURPOSE: To analyze changes in parotid gland dose resulting from anatomic changes throughout a course of radiotherapy in a cohort of head-and-neck cancer patients. METHODS AND MATERIALS: The study population consisted of 10 head-and-neck cancer patients treated definitively with intensity-modulated radiotherapy on a helical tomotherapy unit. A total of 330 daily megavoltage computed tomography images were retrospectively processed through a deformable image registration algorithm to be registered to the planning kilovoltage computed tomography images. The process resulted in deformed parotid contours and voxel mappings for both daily and accumulated dose-volume histogram calculations. The daily and cumulative dose deviations from the original treatment plan were analyzed. Correlations between dosimetric variations and anatomic changes were investigated. RESULTS: The daily parotid mean dose of the 10 patients differed from the plan dose by an average of 15%. At the end of the treatment, 3 of the 10 patients were estimated to have received a greater than 10% higher mean parotid dose than in the original plan (range, 13-42%), whereas the remaining 7 patients received doses that differed by less than 10% (range, -6-8%). The dose difference was correlated with a migration of the parotids toward the high-dose region. CONCLUSIONS: The use of deformable image registration techniques and daily megavoltage computed tomography imaging makes it possible to calculate daily and accumulated dose-volume histograms. Significant dose variations were observed as result of interfractional anatomic changes. These techniques enable the implementation of dose-adaptive radiotherapy.

Evaluation of image-guidance strategies in the treatment of localized prostate cancer.

PURPOSE: To compare different image-guidance strategies in the alignment of prostate cancer patients. Using data from patients treated using daily image guidance, the remaining setup errors for several different strategies were retrospectively calculated. METHODS AND MATERIALS: The alignment data from 74 patients treated with helical tomotherapy were analyzed, resulting in a data set of 2,252 fractions during which a megavoltage computed tomography image was used for image guidance with intraprostatic metallic fiducials. Given the daily positional adjustments, a variety of protocols, differing in imaging frequency and method, were retrospectively studied. The residual setup errors were determined for each protocol. RESULTS: As expected, the systematic errors were effectively reduced with imaging. However, the random errors were unaffected. Even when image guidance was performed every other day with a running mean of the previous displacements, residual setup errors>5 mm occurred in 24% of all fractions. This frequency increased to about 40% if setup errors>3 mm were scored. CONCLUSION: Setup errors increased with decreasing frequency of image guidance. However, residual errors were still significant at the 5-mm level, even with imaging was performed every other day. This suggests that localizations must be performed daily in the set up of prostate cancer patients during a course of external beam radiotherapy.

Implantation and stability of metallic fiducials within pulmonary lesions.

PURPOSE: To report and describe implantation techniques and stability of metallic fiducials in lung lesions to be treated with external beam radiotherapy. METHODS AND MATERIALS: Patients undergoing radiation therapy for small early-stage lung cancer underwent implantation with small metallic markers. Implantation was either transcutaneous under computed tomographic (CT) or fluoroscopic guidance or transbronchial with the superDimension/Bronchus system (radiofrequency signal-based bronchoscopy guidance related to CT images). RESULTS: Implantation was performed transcutaneously in 15 patients and transbronchially in 8 patients. Pneumothorax occurred with eight of the 15 transcutaneous implants, six of which required chest tube placement. None of the patients who underwent transbronchial implantation developed pneumothorax. Successfully inserted markers were all usable during gated image-guided radiotherapy. Marker stability was determined by observing the variation in gross target volume (GTV) centroid relative to the marker on repeated CT scans. Average three-dimensional variation in the GTV center relative to the marker was 2.6 +/- 1.3 (SD) mm, and the largest variation along any anatomic axis for any patient was <5 mm. Average GTV volume decrease during the observation period was 34% +/- 23%. Gross tumor volumes do not appear to shrink uniformly about the center of the tumor, but rather the tumor shapes deform substantially throughout treatment. CONCLUSIONS: Transbronchial marker placement is less invasive than transcutaneous placement, which is associated with high pneumothorax rates. Although marker geometry can be affected by tumor shrinkage, implanted markers are stable within tumors throughout the treatment duration regardless of implantation method.

Evaluation of image-guidance protocols in the treatment of head and neck cancers.

PURPOSE: The aim of this study was to assess the residual setup error of different image-guidance (IG) protocols in the alignment of patients with head and neck cancer. The protocols differ in the percentage of treatment fractions that are associated with image guidance. Using data from patients who were treated with daily IG, the residual setup errors for several different protocols are retrospectively calculated. METHODS AND MATERIALS: Alignment data from 24 patients (802 fractions) treated with daily IG on a helical tomotherapy unit were analyzed. The difference between the daily setup correction and the setup correction that would have been made according to a specific protocol was used to calculate the residual setup errors for each protocol. RESULTS: The different protocols are generally effective in reducing systematic setup errors. Random setup errors are generally not reduced for fractions that are not image guided. As a consequence, if every other treatment is image guided, still about 11% of all treatments (IG and not IG) are subject to three-dimensional setup errors of at least 5 mm. This frequency increases to about 29% if setup errors >3 mm are scored. For various protocols that require 15% to 31% of the treatments to be image guided, from 50% to 60% and from 26% to 31% of all fractions are subject to setup errors >3 mm and >5 mm, respectively. CONCLUSION: Residual setup errors reduce with increasing frequency of IG during the course of external-beam radiotherapy for head-and-neck cancer patients. The inability to reduce random setup errors for fractions that are not image guided results in notable residual setup errors.

Feasibility study of helical tomotherapy for total body or total marrow irradiation.

Total body radiation (TBI) has been used for many years as a preconditioning agent before bone marrow transplantation. Many side effects still plague its use. We investigated the planning and delivery of total body irradiation (TBI) and selective total marrow irradiation (TMI) and a reduced radiation dose to sensitive structures using image-guided helical tomotherapy. To assess the feasibility of using helical tomotherapy, (A) we studied variations in pitch, field width, and modulation factor on total body and total marrow helical tomotherapy treatments. We varied these parameters to provide a uniform dose along with a treatment times similar to conventional TBI (15-30 min). (B) We also investigated limited (head, chest, and pelvis) megavoltage CT (MVCT) scanning for the dimensional pretreatment setup verification rather than total body MVCT scanning to shorten the overall treatment time per treatment fraction. (C) We placed thermoluminescent detectors (TLDs) inside a Rando phantom to measure the dose at seven anatomical sites, including the lungs. A simulated TBI treatment showed homogeneous dose coverage (+/-10%) to the whole body. Doses to the sensitive organs were reduced by 35%-70% of the target dose. TLD measurements on Rando showed an accurate dose delivery (+/-7%) to the target and critical organs. In the TMI study, the dose was delivered conformally to the bone marrow only. The TBI and TMI treatment delivery time was reduced (by 50%) by increasing the field width from 2.5 to 5.0 cm in the inferior-superior direction. A limited MVCT reduced the target localization time 60% compared to whole body MVCT. MVCT image-guided helical tomotherapy offers a novel method to deliver a precise, homogeneous radiation dose to the whole body target while reducing the dose significantly to all critical organs. A judicious selection of pitch, modulation factor, and field size is required to produce a homogeneous dose distribution along with an acceptable treatment time. In addition, conformal radiation to the bone marrow appears feasible in an external radiation treatment using image-guided helical tomotherapy.

Potential for radiation therapy technology innovations to permit dose escalation for non-small-cell lung cancer.

BACKGROUND: Innovations in radiation therapy (RT) technology could have the potential to allow for radiation dose escalation by evaluating tumor motion, minimizing and compensating for motion, and evaluating delivery technologies such as 3-dimensional (3D) conformal radiation therapy (CRT) and intensity-modulated RT (IMRT) using tomotherapy. MATERIALS AND METHODS: Ninety different RT plans were generated using 3 different treatment techniques for 10 patients. These were evaluated using dosimetric tools such as dose-volume histogram (DVH) analysis, tumor equivalent uniform dose (EUD), and dosimetric parameters predictive for lung toxicity, such as the volume of lung receiving > 20 Gy of radiation (V20) and the normalized mean total radiation dose to the lung (NTDmean). The 3 techniques studied included free breathing using 3D CRT, 3D CRT with maximum-inspiration breath-hold (MIBH) to minimize tumor motion, and IMRT delivery with MIBH; the combination of 3 separate planning treatment-volume sets resulted in the generation of 90 different treatment plans. To plan these, patients underwent treatment-planning computed tomography in MIBH and free breathing followed by simulation with measurement of tumor motion and generation/evaluation of DVHs, EUDs, V20, and NTDmean. RESULTS: Average tumor motion was 1.54 cm in the cephalocaudad directions, 1.26 cm in the anteroposterior directions, and 0.56 cm in the lateral directions between maximum inspiration and expiration. Maximum-inspiration breath-hold produced superior lung sparing evidenced by lower V20 and NTDmean values, and these parameters predicted lower modeled pneumonitis rates. Tomotherapy-based IMRT provided further lung sparing. CONCLUSION: Treatment in MIBH results in lower V20 and NTDmean values and lower modeled pneumonitis rates. This effect is enhanced by the use of IMRT. The use of MIBH with IMRT may therefore aid in escalating the dose in RT.