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Purpose: PTW's Octavius 1000 SRS array performs IMRT QA measurements with liquid filled ionization chambers (LICs). Collection efficiencies of LICs have been shown to change during IMRT delivery as a function of LINAC pulse frequency and pulse dose, which affects QA results. In this study, two methods were developed to correct changes in collection efficiencies during IMRT QA measurements, and the effects of these corrections on QA pass rates were compared. Methods: For the first correction, Matlab software was developed that calculates pulse frequency and pulse dose for each detector, using measurement and DICOM RT Plan files. Pulse information is converted to collection efficiency and measurements are corrected by multiplying detector dose by ratios of calibration to measured collection efficiencies. For the second correction, MU/min in daily 1000 SRS calibration was chosen to match average MU/min of the VMAT plan. Usefulness of derived corrections were evaluated using 6MV and 10FFF SBRT RapidArc plans delivered to the OCTAVIUS 4D system using a TrueBeam equipped with an HD- MLC. Effects of the two corrections on QA results were examined by performing 3D gamma analysis comparing predicted to measured dose, with and without corrections. Results: After complex Matlab corrections, average 3D gamma pass rates improved by [0.07%,0.40%,1.17%] for 6MV and [0.29%,1.40%,4.57%] for 10FFF using [3%/3mm,2%/2mm,1%/1mm] criteria. Maximum changes in gamma pass rates were [0.43%,1.63%,3.05%] for 6MV and [1.00%,4.80%,11.2%] for 10FFF using [3%/3mm,2%/2mm,1%/1mm] criteria. On average, pass rates of simple daily calibration corrections were within 1% of complex Matlab corrections. Conclusion: Ion recombination effects can potentially be clinically significant for OCTAVIUS 1000 SRS measurements, especially for higher pulse dose unflattened beams when using tighter gamma tolerances. Matching daily 1000 SRS calibration MU/min to average planned MU/min is a simple correction that greatly reduces ion recombination effects, improving measurements accuracy and gamma pass rates. This work was supported by PTW.

Importance Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18 F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. Objective To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). Design, Setting, and Participants A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. Intervention Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. Main Outcomes and Measures The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. Results The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45-83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63-86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%-92%) and 62% (95% CI, 43%-77%), respectively. Median overall survival was 25 months (95% CI, 12-32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%-66%) and 30% (95% CI, 16%-45%), respectively. Conclusions and Relevance Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. Trial Registration clinicaltrials.gov Identifier:NCT01190527

Purpose To investigate whether high-dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Methods and Materials Patients with medically inoperable/unresectable NSCLC treated with definitive radiation therapy in prospective studies were eligible for this study. Pulmonary artery involvement was defined on the basis of pretreatment chest CT and positron emission tomography/CT fusion. Pulmonary artery was contoured according to the Radiation Therapy Oncology Group protocol 1106 atlas, and dose-volume histograms were generated. Results A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiation therapy. Radiation dose ranged from 60 to 85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤2, 3, 4, and 5 had 1-year OS and median survival of 67% and 25.4 months (95% confidence interval [CI] 15.7-35.1), 62% and 22.2 months (95% CI 5.8-38.6), 90% and 35.8 months (95% CI 28.4-43.2), and 50% and 7.0 months, respectively ( P =.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of radiation therapy. Maximum and mean doses to PA were not significantly associated with OS. The V45, V50, V55, and V60 of PA were correlated significantly with a worse OS ( P 70% or V60 >37% had significantly worse OS (13.3 vs 37.9 months, P P =.04, respectively). Conclusions Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.

This study aims at developing and testing a novel rigidity penalty suitable for the deformable registration of tightly located skeletal components in the head and neck from planning computed tomography (CT) and daily cone-beam CT (CBCT) scans of patients undergoing radiotherapy.The proposed rigidity penalty is designed to preserve intervoxel distances within each bony structure. This penalty was tested in the intensity-based B-spline deformable registration of five cervical vertebral bodies (C1-C5). The displacement vector fields (DVFs) from the registrations were compared to the DVFs generated by using rigid body motions of the cervical vertebrae, measured by the surface registration of vertebrae delineated on CT and CBCT images. Twenty five pairs of planning CT (reference) and treatment CBCTs (target) from five patients were aligned without and with the penalty. An existing penalty based on the orthonormality of the deformation gradient tensor was also tested and the effects of the penalties compared.The mean magnitude of the maximum registration error with the proposed distance-preserving penalty was (0.86, 1.12, 1.33) mm compared to (2.11, 2.49, 2.46) without penalty and (1.53, 1.64, 1.64) with the existing orthonormality-based penalty. The improvement in the accuracy of the deformable image registration was also verified by comparing the Procrustes distance between the DVFs. With the proposed penalty, the average distance was 0.11 (σ 0.03 mm) which is smaller than 0.53 (0.1 mm) without penalty and 0.28 (0.04 mm) with the orthonormality-based penalty.The accuracy of aligning multiple bony elements was improved by using the proposed distance-preserving rigidity penalty. The voxel-based statistical analysis of the registration error shows that the proposed penalty improved the integrity of the DVFs within the vertebral bodies.

Purpose: Liver SBRT patients have variable pre-treatment liver function, which strongly influences liver toxicity risk. Previous studies include a “perfusion-weighted” mean dose model as a surrogate for liver function in plan optimization. This work investigates the benefit of using a more sophisticated dose-response model that incorporates two important dose thresholds: (i) based on pre-treatment function, a significant low-dose may need to be exceeded before noticeable damage is done, and (ii) a high-dose saturation point, beyond which no additional damage is done. Methods: Voxel-based liver perfusion from DCE-MRI was obtained. Two optimization models subject to the same linear dose constraints (e.g., minimum target EUD, maximum critical structure dose) were compared: the original linear model, which use pre-treatment perfusion-weighted mean liver dose only, and a new model designed to directly optimize the predicted post-treatment global liver function. The latter, a highly non-linear non-convex problem, was approximately solved by optimizing a piece-wise linear approximation of the objective function with a customized mixed-integer linear programming (MILP) based algorithm. 2D synthetic and 3D clinical cases were studied to assess the potential benefit of the new model. Results: Compared to those of the original model, dose distributions for the functional dose response model take advantage of voxels with saturated damage to deliver the required dose to the target instead of inflicting additional damage on other well-functioning voxels. This leads to an improvement in predicted post-treatment global liver function. The customized solution method also improves optimization efficiency compared to solving the MILP conventionally. Conclusion: Functional imaging such as DCE-MRI can be used during treatment planning to maximize potential post-treatment function. However, simple approximations such as minimization of perfusion-weighted mean dose may not be sufficient. Alternatively, a dose-response model that reflects response threshold and saturation effects was shown to improve the prediction of post-treatment function in liver SBRT. Supported by P01 CA 059827

Purpose: Overall low dose to lung for patients with locally advanced lung cancer with large PTVs is a concern, prompting investigation into the preferred arc geometry for lung VMAT. Methods: 8 subjects (6 males, 64±7 years, stage III/IV=5/3) were enrolled with a mean PTV size of 595±303cc. A standard dose scheme of 60Gy in 30 fractions was used for all subjects. For each subject, four VMAT plans with different combinations of the number of arcs (1 arc vs. two arcs) and the arc range (full vs. partial arc) were generated in Eclipse. Dosimetric characteristics for each plan were evaluated by PTV coverage and OAR sparing. PTV coverage was quantified by mean, max dose, homogeneity index HI5/95 defined as (D5%–D95%)/Mean_dose and conformity index (CI). OAR sparing was measured by mean, V10 and V20 for lung minus GTV, mean, max, V30 and V40 for heart and max dose for cord. For each metric abovementioned, a two-way repeated ANOVA analysis was performed to evaluate whether the number of arcs and the arc range will significantly affect dose distribution of VMAT plans. Results: In general partial arc geometry provided better PTV coverage with significantly smaller HI5/95 (p

To introduce a hybrid volumetric modulated arc therapy/intensity modulated radiation therapy (VMAT/IMRT) optimization strategy called FusionArc that combines the delivery efficiency of single-arc VMAT with the potentially desirable intensity modulation possible with IMRT.A beamlet-based inverse planning system was enhanced to combine the advantages of VMAT and IMRT into one comprehensive technique. In the hybrid strategy, baseline single-arc VMAT plans are optimized and then the current cost function gradients with respect to the beamlets are used to define a metric for predicting which beam angles would benefit from further intensity modulation. Beams with the highest metric values (called the gradient factor) are converted from VMAT apertures to IMRT fluence, and the optimization proceeds with the mixed variable set until convergence or until additional beams are selected for conversion. One phantom and two clinical cases were used to validate the gradient factor and characterize the FusionArc strategy. Comparisons were made between standard IMRT, single-arc VMAT, and FusionArc plans with one to five IMRT∕hybrid beams.The gradient factor was found to be highly predictive of the VMAT angles that would benefit plan quality the most from beam modulation. Over the three cases studied, a FusionArc plan with three converted beams achieved superior dosimetric quality with reductions in final cost ranging from 26.4% to 48.1% compared to single-arc VMAT. Additionally, the three beam FusionArc plans required 22.4%-43.7% fewer MU∕Gy than a seven beam IMRT plan. While the FusionArc plans with five converted beams offer larger reductions in final cost--32.9%-55.2% compared to single-arc VMAT--the decrease in MU∕Gy compared to IMRT was noticeably smaller at 12.2%-18.5%, when compared to IMRT.A hybrid VMAT∕IMRT strategy was implemented to find a high quality compromise between gantry-angle and intensity-based degrees of freedom. This optimization method will allow patients to be simultaneously planned for dosimetric quality and delivery efficiency without switching between delivery techniques. Example phantom and clinical cases suggest that the conversion of only three VMAT segments to modulated beams may result in a good combination of quality and efficiency.

Plan degradation resulting from compromises made to enhance delivery efficiency is an important consideration for intensity modulated radiation therapy (IMRT) treatment plans. IMRT optimization and/or multileaf collimator (MLC) sequencing schemes can be modified to generate more efficient treatment delivery, but the effect those modifications have on plan quality is often difficult to quantify. In this work, the authors present a method for quantitative assessment of overall plan quality degradation due to tradeoffs between delivery efficiency and treatment plan quality, illustrated using comparisons between plans developed allowing different numbers of intensity levels in IMRT optimization and/or MLC sequencing for static segmental MLC IMRT plans.A plan quality degradation method to evaluate delivery efficiency and plan quality tradeoffs was developed and used to assess planning for 14 prostate and 12 head and neck patients treated with static IMRT. Plan quality was evaluated using a physician's predetermined "quality degradation" factors for relevant clinical plan metrics associated with the plan optimization strategy. Delivery efficiency and plan quality were assessed for a range of optimization and sequencing limitations. The "optimal" (baseline) plan for each case was derived using a clinical cost function with an unlimited number of intensity levels. These plans were sequenced with a clinical MLC leaf sequencer which uses100 segments, assuring delivered intensities to be within 1% of the optimized intensity pattern. Each patient's optimal plan was also sequenced limiting the number of intensity levels (20, 10, and 5), and then separately optimized with these same numbers of intensity levels. Delivery time was measured for all plans, and direct evaluation of the tradeoffs between delivery time and plan degradation was performed.When considering tradeoffs, the optimal number of intensity levels depends on the treatment site and on the stage in the process at which the levels are limited. The cost of improved delivery efficiency, in terms of plan quality degradation, increased as the number of intensity levels in the sequencer or optimizer decreased. The degradation was more substantial for the head and neck cases relative to the prostate cases, particularly when fewer than 20 intensity levels were used. Plan quality degradation was less severe when the number of intensity levels was limited in the optimizer rather than the sequencer.Analysis of plan quality degradation allows for a quantitative assessment of the compromises in clinical plan quality as delivery efficiency is improved, in order to determine the optimal delivery settings. The technique is based on physician-determined quality degradation factors and can be extended to other clinical situations where investigation of various tradeoffs is warranted.

Purpose: There is potentially a wide variation in plan quality for a certain disease site, even for clinics located in the same system of hospitals. We have used a prostate-specific knowledge-based planning (KBP) model as a quality control tool to investigate the variation in prostate treatment planning across a network of affiliated radiation oncology departments. Methods: A previously created KBP model was applied to 10 patients each from 4 community-based clinics (Clinics A, B, C, and D). The KBP model was developed using RapidPlan (Eclipse v13.5, Varian Medical Systems) from 60 prostate/prostate bed IMRT plans that were originally planned using an in-house treatment planning system at the central institution of the community-based clinics. The dosimetric plan quality (target coverage and normal-tissue sparing) of each model-generated plan was compared to the respective clinically-used plan. Each community-based clinic utilized the same planning goals to develop the clinically-used plans that were used at the main institution. Results: Across all 4 clinics, the model-generated plans decreased the mean dose to the rectum by varying amounts (on average, 12.5, 2.6, 4.5, and 2.7 Gy for Clinics A, B, C, and D, respectively). The mean dose to the bladder also decreased with the model-generated plans (5.4, 2.3, 3.0, and 4.1 Gy, respectively). The KBP model also identified that target coverage (D95%) improvements were possible for for Clinics A, B, and D (0.12, 1.65, and 2.75%) while target coverage decreased by 0.72% for Clinic C, demonstrating potentially different trade-offs made in clinical plans at different institutions. Conclusion: Quality control of dosimetric plan quality across a system of radiation oncology practices is possible with knowledge-based planning. By using a quality KBP model, smaller community-based clinics can potentially identify the areas of their treatment plans that may be improved, whether it be in normal-tissue sparing or improved target coverage. M. Matuszak has research funding for KBP from Varian Medical Systems

Purpose: To date, lung CT-ventilation imaging has been based on quantification of local breathing-induced changes in Hounsfield Units (HU) or volume. This work investigates the use of a stress map resulting from a biomechanical deformable image registration (DIR) algorithm as a metric of the ventilation function. Method: Eight lung cancer patients presenting different kinds of ventilation defects were retrospectively analyzed. Additionally, to the 4DCT acquired for radiotherapy planning, five of them had PET and three had SPECT imaging following inhalation of Ga-68 and Tc-99m, respectively. For each patient, the inhale phase of the 4DCT was registered to the exhale phase using Morfeus, a biomechanical DIR algorithm based on the determination of boundary conditions on the lung surfaces and vessel tree. To take into account the heterogeneity of the tissue stiffness in the stress map estimation, each tetrahedral element of the finite-element model was assigned a Young's modulus ranging from 60kPa to 12MPa, as a function of the HU in the inhale CT. The node displacements and element stresses resulting from the numerical simulation were used to generate three CT-ventilation maps based on: (i) volume changes (Jacobian determinant), (ii) changes in HU, (iii) the maximum principal stress. The voxel-wise correlation between each CT-ventilation map and the PET or SPECT V image was computed in a lung mask. Results: For patients with PET, the mean (min-max) Spearman correlation coefficients r were: 0.33 (0.19–0.45), 0.36 (0.16–0.51) and 0.42 (0.21–0.59) considering the Jacobian, changes in HU and maximum principal stress, respectively. For patients with SPECT V, the mean r were: 0.12 (−0.12–0.43), 0.29 (0.22–0.45) and 0.33 (0.25–0.39). Conclusion: The maximum principal stress maps showed a stronger correlation with the ventilation images than the previously proposed Jacobian or change in HU maps. This metric thus appears promising for CT-ventilation imaging. This work was funded in part by NIH P01CA059827.

Purpose: With electronic medical records, patient information for the treatment planning process has become disseminated across multiple applications with limited quality control and many associated failure modes. We present the development of a single application with a centralized database to manage the planning process. Methods: The system was designed to replace current functionalities of (i) static directives representing the physician intent for the prescription and planning goals, localization information for delivery, and other information, (ii) planning objective reports, (iii) localization and image guidance documents and (iv) the official radiation therapy prescription in the medical record. Using the Eclipse Scripting Application Programming Interface, a plug-in script with an associated domain-specific SQL Server database was created to manage the information in (i)–(iv). The system's user interface and database were designed by a team of physicians, clinical physicists, database experts, and software engineers to ensure usability and robustness for clinical use. Results: The resulting system has been fully integrated within the TPS via a custom script and database. Planning scenario templates, version control, approvals, and logic-based quality control allow this system to fully track and document the planning process as well as physician approval of tradeoffs while improving the consistency of the data. Multiple plans and prescriptions are supported along with non-traditional dose objectives and evaluation such as biologically corrected models, composite dose limits, and management of localization goals. User-specific custom views were developed for the attending physician review, physicist plan checks, treating therapists, and peer review in chart rounds. Conclusion: A method was developed to maintain cohesive information throughout the planning process within one integrated system by using a custom treatment planning management application that interfaces directly with the TPS. Future work includes quantifying the improvements in quality, safety and efficiency that are possible with the routine clinical use of this system. Supported in part by NIH-P01-CA-059827

Purpose: NSCLC radiotherapy treatment is a trade-off between controlling the tumor while limiting radiation-induced toxicities. Here we identify hierarchical biophysical relationships that could simultaneously influence both local control (LC) and RP by using an integrated Bayesian Networks (BN) approach. Methods: We studied 79 NSCLC patients treated on prospective protocol with 56 cases of LC and 21 events of RP. Beyond dosimetric information, each patient had 193 features including 12 clinical factors, 60 circulating blood cytokines before and during radiotherapy, 62 microRNAs, and 59 single-nucleotide polymorphisms (SNPs). The most relevant biophysical predictors for both LC and RP were identified using a Markov blanket local discovery algorithm and the corresponding BN was constructed using a score-learning algorithm. The area under the free-response receiver operating characteristics (AU-FROC) was used for performance evaluation. Cross-validation was employed to guard against overfitting pitfalls. Results: A BN revealing the biophysical interrelationships jointly in terms of LC and RP was developed and evaluated. The integrated BN included two SNPs, one microRNA, one clinical factor, three pre-treatment cytokines, relative changes of two cytokines between pre and during-treatment, and gEUDs of the GTV (a=-20) and lung (a=1). On cross-validation, the AUC prediction of independent LC was 0.85 (95% CI: 0.75–0.95) and RP was 0.83 (0.73–0.92). The AU-FROC of the integrated BN to predict both LC/RP was 0.81 (0.71–0.90) based on 2000 stratified bootstrap, indicating minimal loss in joint prediction power. Conclusions: We developed a new approach for multiple outcome utility application in radiotherapy based on integrated BN techniques. The BN developed from large-scale retrospective data is able to simultaneously predict LC and RP in NSCLC treatments based on individual patient characteristics. The joint prediction is only slightly compromised compared to independent predictions. Our approach shows promise for use in clinical decision support system for personalized radiotherapy subject to multiple endpoints. These studies were supported by a grant from the NCI/NIH P01-CA59827.

Purpose: To extend the functionality of a commercial treatment planning system (TPS) to support (i) direct use of quantitative image-based metrics within treatment plan optimization and (ii) evaluation of dose-functional volume relationships to assist in functional image adaptive radiotherapy. Methods: A script was written that interfaces with a commercial TPS via an Application Programming Interface (API). The script executes a program that performs dose-functional volume analyses. Written in C#, the script reads the dose grid and correlates it with image data on a voxel-by-voxel basis through API extensions that can access registration transforms. A user interface was designed through WinForms to input parameters and display results. To test the performance of this program, image- and dose-based metrics computed from perfusion SPECT images aligned to the treatment planning CT were generated, validated, and compared. Results: The integration of image analysis information was successfully implemented as a plug-in to a commercial TPS. Perfusion SPECT images were used to validate the calculation and display of image-based metrics as well as dose-intensity metrics and histograms for defined structures on the treatment planning CT. Various biological dose correction models, custom image-based metrics, dose-intensity computations, and dose-intensity histograms were applied to analyze the image-dose profile. Conclusion: It is possible to add image analysis features to commercial TPSs through custom scripting applications. A tool was developed to enable the evaluation of image-intensity-based metrics in the context of functional targeting and avoidance. In addition to providing dose-intensity metrics and histograms that can be easily extracted from a plan database and correlated with outcomes, the system can also be extended to a plug-in optimization system, which can directly use the computed metrics for optimization of post-treatment tumor or normal tissue response models. Supported by NIH - P01 - CA059827

Purpose: To make Image Guided Radiation Therapy (IGRT) credentialing a more unified, consistent and efficient process across the entire National Clinical Trial Network (NCTN). Methods: IGRT plays a role in several advanced NCTN trials. Previously an institution had to be IGRT credentialed for each protocol. When institutions were allowed to use previous credentials for new protocols it was limited to the same disease site as the original credentialing. The credentialing was analyzed by the physics PI of the protocol. We consulted with several of these physicists to determine what is important to consider when reviewing submissions and to learn ways to apply credentialing more broadly. Results: For trials open in 2016, IGRT credentialing can be simplified to cover either boney anatomy or soft tissue. This revised credentialing will cover all disease sites based on the type of anatomy, unless otherwise stated within the protocol. Institutions will submit will complete an online questionnaire about their IGRT procedures. Boney anatomy requirements will include submission of data from 2 sequential fraction of both a patient aligned with boney anatomy and pelvic patient. Soft tissue will require similar submissions for a patient aligned using soft tissue and a pelvic patient. Institutions will only be required to submit the pelvic patient once. Data should be in DICOM format and includes planning CT set, RT structure set, RT plan file, RT dose file, localization images and spatial registration file (if available). Reviews will be done by IROC-Houston staff who will continue to provide feedback to the sites. Conclusion: This revised IGRT credentialing process will bring consistency, a savings in time and effort for both the IROC Houston QA office and to those institutions wanting to be credentialed to participate in NCTN Trials. Sponsored by NIH/NCI CA10953

Purpose: Interfraction changes in abdominal SBRT patient anatomy are challenging to address with image guidance alone because avoidance of an overlapping high-priority gastrointestinal normal structure may come at the expense of tumor coverage. This work investigates the benefit of anticipating interfraction motion and exploiting favorable geometries at the time of treatment through dose adaptive planning. Methods: Beyond no change, six scenarios of duodenum shifts per fraction are generated (±1 cm XYZ) and sample five-fraction paths (combinations of no and/or the indicated changes) are simulated. Under the baseline (nominal) plan, generated assuming no uncertainty, three scenarios result in overdosing the duodenum while the others result in safe or reduced dose. The nominal plan under-doses the PTV (36.1 Gy-EQD2) due to duodenum proximity. Three adaptive strategies are considered: i) Standard IGRT: for duodenum overdose, patient's isocenter is shifted to satisfy the duodenum dose tolerance; nominal plan is delivered otherwise; ii) Scaling: nominal plan scaled up/down in favorable/unfavorable patient geometries; iii) Mixed: shifting as in i) but boosting otherwise. If max duodenum dose (limit 6 Gy/Fx) is exceeded, dose distributions are shifted or scaled down, depending on the strategy considered. In all adaptive fractions, critical structure dose limits are satisfied, even if the PTVs are under-dosed. Results: Generally, scaling dose allows better PTV dose (gEUD in Gy-EQD2); however, in some scenarios, shifting is better than scaling down dose. In a path with 2 fractions of the duodenum not moving and 3 fractions of an unfavorable duodenum position, scaling dose results in the best coverage, with 36.8 Gy-EQD2. In another path with 2 favorable and 3 unfavorable duodenum positions, the mixed strategy achieves the highest coverage with 41.0 Gy-EQD2. Conclusions: Anticipating interfraction motion and exploiting favorable geometries through dose adaptive scaling can improve overall tumor coverage by compensating for conservative IGRT in unfavorable fractions. NIH-P01-CA059827

TPS1098Background: This randomized Phase II trial evaluates if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received, or planned to receive, up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met, a phase III component evaluates if SBRT/SR improves 5 year OS. Secondary aims include local control in the metastases, new metastases, and technical quality. Translational primary endpoint is to determine whether < 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: A 2016 amendment expanded eligibility criteria to pathologically confirmed metastatic breast cancer to ≤ 2 sites and < 12 months of standard first line systemic therapy. Registration must occur

Background: The current standard of care for metastatic breast cancer patients (pts) is to deliver palliative chemotherapy, biologic &/or hormonal therapy when appropriate, with radiation &/or surgery reserved for the management of symptomatic or non-responsive (mets). For selected pts with limited metastatic (met) disease, mets-directed ablative therapy, with either surgical resection or high dose conformal radiotherapy (in addition to standard systemic therapies) to lung, liver, CNS adrenal, & multiple organs has been shown to result in long-term disease control numerically superior to systemic therapy alone. NRG-BR002 is a randomized Phase II trial to evaluate stereotactic body radiotherapy (SBRT) &/or surgical resection (SR) of all met sites in newly oligometastatic breast cancer in addition to standard systemic therapy. Trial Design & Eligibility For the Ph IIR, eligible breast cancer pts who have received up to 6 months of first line systemic therapy without progression will be randomized to receive either standard systemic therapy with mets directed therapy as needed ( control arm) versus ablative therapy of all met sites with either body SBRT &/or surgical resection (SR) ( per the treating physician discretion) to determine if there is an improvement median progression free survival (PFS). If this aim is met the trial continues as a Ph III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the met site, new distant met rate, & technical quality. The primary translational endpoint tests whether < 5 CTCs (per 7.5ml of blood) is an independent prognostic (outcome) marker for improved PFS & OS in oligometastatic breast cancer. Women with pathologically confirmed met breast cancer to < /= 2 sites, with up to 6 months of standard first line systemic therapy & the primary site disease is controlled. CNS mets are ineligible. ER/PR & HER-2 neu are required on either the primary or met site. Site radiation credentialing & a facility questionnaire are required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary vs ablative therapy of all mets with SBRT &/or SR. Statistics: For the Ph IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power & accounting for ineligible/lost pts, 146 pts will be required. For the Ph III, an additional 246, for a total of 402 pts will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power & a 1-sided type I error of 0.025. For the translational research, the number of pts accrued in the Ph IIR & Ph III portions will provide sufficient power ≥ 91% to detect whether < 5 CTC's is a prognostic marker for improved PFS & OS. Present Accrual & Target Accrual NRG BR002 activated 12/24/2014 with a target accrual of 146 pts for the Ph II component & 256 additional for the Ph III. Contact Information: Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org. Support: Supported by NRG Oncology grants U10CA180868 & U10CA180822 from the National Cancer Institute (NCI). Citation Format: Chmura SJ, Winter KA, Salama JK, Woodward WA, Borges VF, Al-Hallaq H, Matuszak M, Jaskowiak NT, Milano MT, Bandos H, White JR. NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) &/or surgical ablation for newly oligometastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-03-04.

424 Background: Patients (Pts) with pre-existing liver dysfunction are at high risk for further damage after SBRT. We completed a phase 2 study of individualized SBRT, utilizing pre- and during-treatment indocyanine green (ICG) clearance to adapt treatment and maximize both safety and efficacy. Methods: From 5/10-10/14, pts with hepatocellular carcinoma (HCC) or metastases (mets) were enrolled and underwent SBRT planning up to a target dose of 50-60 Gy or as limited by a 15% normal tissue complication probability for radiation-induced liver disease (RILD). ICG retention at 15 minutes (ICGR15) was measured prior to and 1 month after 3 of 5 planned treatments. Using a Bayesian adaptive model, RT dose was scaled down as necessary for the final 2 treatments to keep ICGR15 < 44% after the full treatment and thus minimize toxicity. Follow up was every 3 months for 2 years. Results: 90 pts received SBRT to 116 tumors and had at least 1 year of potential follow up. Median age was 62 years, range 34-85. 69 had HCC, 4 intrahepatic cholangiocarcinoma, and 17 mets. 62 had cirrhosis, most commonly HCV and alcoholic. Median Child-Pugh (CP) score was 6, range 5-9. 20 pts were CP B/C. Median pre-RT ICGR15 was 22, range 4-75, normal 4-10. Pts had a median of 1.5 (range 0-6) prior liver-directed therapies, most commonly transarterial chemoembolization (70), prior RT (36), and radiofrequency ablation (13). Median tumor size was 3 cm, and 12 had portal vein involvement. 63 received all 5 fractions (48 full dose, 15 with dose reduction due to elevated ICGR15); 27 received only 3 treatments. Median prescription dose was 47 Gy. Treatment was well tolerated with no classical RILD and a lower complication rate than expected without adaptation. 4 pts had grade 3 ascites. 2 pts had GI bleed after SBRT. 14% and 10% of pts experienced at least a 1 or 2 point increase in CP 6 months post SBRT. Local control (95%CI) at 1 and 2 yrs was 99 (96,100)% and 90 (81,100)%. 4 recurrent tumors were 3 HCC and 1 met, measuring 26, 12, 30, 38mm; treated to 30, 50, 33, 30 Gy. Conclusions: Individualized adaptive SBRT, based on ICG clearance is a promising method of allowing pts to receive the maximally aggressive dose based on each pt’s individual tolerance to RT. Funded by P01 CA59827

375 Background: SBRT is emerging as a treatment option for patients with unresectable liver tumors. However, generating high quality liver SBRT plans is technically challenging and user-dependent. Aiming for high tumor doses and low normal tissue doses can demand lengthy planning times and result in plans of inconsistent quality. This study investigates knowledge-based planning (KBP) as a standardized method to ensure efficacy, safety, and efficiency for SBRT plans and allow for broader use of this therapy. Methods: SBRT treatment plans were manually optimized for 55 liver cancer cases by an expert liver dosimetrist in a commercial treatment planning system (Varian Eclipse v13.6). Each volumetric modulated arc therapy plan was approved by a physician using strict criteria for target coverage and normal tissue sparing. The plans were used to create a custom model in a KBP system (RapidPlan, Varian Eclipse v13.6) designed to improve both efficiency and standardization of quality. To validate the model, 15 new cases were optimized manually by an expert liver dosimetrist and then semi-automatically using the KBP model. The validation plans were compared based on target coverage, normal tissue sparing, and planning time. Results: Compared to manual plans created by an expert liver dosimetrist, KBP-generated plans showed similar target coverage and improved normal tissue sparing with similar planning times. Mean and minimum target doses were similar, as was D98, p > 0.2 for all. Normal tissue complication probability for liver damage was marginally lower with KBP, mean 3 vs. 1%, p = 0.07. Doses to adjacent organs including stomach, heart, and bowel were similar. Manual planning required a median and mean time of 15 and 20 minutes, respectively, range 8-55 min. KBP required similar times of 12 and 19 min, range 8-50 min. 9 of 15 KBP cases were automated, while 6 plans required dosimetrist improvement. Conclusions: Using KBP, high quality plans for liver SBRT can be created automatically or semi-automatically. These plans are comparable to those generated by an expert liver dosimetrist. KBP could be used to standardize treatments between institutions, particularly when experience with liver SBRT is limited.

A new rigidity penalty was developed to improve the accuracy of an intensity-based B-spline deformable image registration, and its impact on the displacement vector field (DVF) within cervical vertebrae was investigated. The developed rigidity penalty was tested on ten (10) pairs of cone-beam computed tomography (CBCT) scans. The results were compared to those with a conventional rigidity penalty based on the orthonormality of the deformation gradient tensor. The registration error calculated on the DVFs with both penalties was defined as the distance from the ground-truth DVFs obtained by aligning surface models of the pairs of the image data sets. The ability of the image registration methods to cover multiple rigid body motions was evaluated by using orthogonal Procrustes analysis. The results show that the new rigidity penalty better discouraged local deformation within the skeletal components than the conventional orthonormality penalty.

Purpose/objective(s) Volumetric modulated arc therapy (VMAT) allows for intensity-modulated radiation delivery during gantry rotation with dynamic MLC motion, variable dose rates and gantry speed modulation. We compared VMAT plans with 3D-CRT for hypofractionated lung radiotherapy. Materials/methods Twenty-one 3D-CRT plans for Stage IA lung cancer previously treated stereotactically were selected. VMAT plans were generated by optimizing machine aperture shape and radiation intensity at 10° intervals. A partial arc range of 180° was manually selected to coincide with tumor location. The arc was resampled down to 5° intervals to ensure dose calculation accuracy. Identical planning objectives were used for VMAT/3D-CRT. Parameters assessed included dose to PTV and organs-at-risk (OAR), monitor units, and multiple conformity and homogeneity indices. Plans were delivered to a phantom for time comparison. Results Lung V20/12.5/10/5 were less with VMAT (relative reduction 4.5%, p = .02; 3.2%, p = .01; 2.6%, p = .01; 4.2%, p = .03, respectively). Mean/maximum-doses to PTV, dose to additional OARs, 95% isodose line conformity, and target volume homogeneity were equivalent. VMAT improved conformity at both the 80% (1.87 vs. 1.93, p = .08) and 50% isodose lines (5.19 vs. 5.65, p = .01). Treatment times were reduced significantly with VMAT (mean 6.1 vs. 11.9 min, p Conclusions Single arc VMAT planning achieves highly conformal dose distributions while controlling dose to critical structures, including significant reduction in lung dose volume parameters. Employing a VMAT technique decreases treatment times by 37–63%, reducing the chance of error introduced by intrafraction variation. The quality and efficiency of VMAT is ideally suited for stereotactic lung radiotherapy delivery.