A study of the dosimetric impact of daily setup variations measured with cone-beam CT on three-dimensional conformal radiotherapy for early-stage breast cancer delivered in the prone position.

PURPOSE: To evaluate the dosimetric impact of daily positioning variations measured with cone-beam computed tomography (CBCT) on whole-breast radiotherapy patients treated in the prone position. METHODS: Daily CBCT was prospectively acquired for 30 consecutive patients positioned prone. Treatment for early-stage (≤II) breast cancer was prescribed with standard dose (50 Gy/25 fractions) or hypofractionation (42.56 Gy/16 fractions) for 13 and 17 patients, respectively. Systematic and random errors were calculated from the translational CBCT shifts and used to determine population-based setup margins. Mean translations (±one standard deviation) for each patient were used to simulate the dosimetric impact on targets (PTV_eval and lumpectomy cavity), heart, and lung. Paired Student's t tests at α = 0.01 were used to compare dose metrics after correction for multiple testing (P < 0.002). Significant correlation coefficients were used to identify associations (P < 0.01). RESULTS: Of 597 total fractions, 20 ± 13% required patient rotation. Mean translations were 0.29 ± 0.27 cm, 0.41 ± 0.34 cm, and 0.48 ± 0.33 cm in the anterior-posterior, superior-inferior, and lateral directions leading to calculated setup margins of 0.63, 0.88, and 1.10 cm, respectively. Average three-dimensional (3D) shifts correlated with the maximum distance of breast tissue from the sternum (r = 0.62) but not with body-mass index. Simulated shifts showed significant, but minor, changes in dose metrics for PTV_eval, lung, and heart. For left-sided treatments (n = 18), mean heart dose increased from 109 ± 75 cGy to 148 ± 115 cGy. Shifts from the original plan caused PTV_eval hotspots (V105%) to increase by 5.2% ± 3.8%, which correlated with the total MU of wedged fields (r = 0.59). No significant change in V95% to the cavity was found. CONCLUSIONS: Large translational variations that occur when positioning prone breast patients had small but significant dosimetric effects on 3DCRT plans. Daily CBCT may still be necessary to correct for rotational variations that occur in 20% of treatments. To maintain planned dose metrics, unintended beam shifts toward the heart and the contribution of wedged fields should be minimized.

A survey of surface imaging use in radiation oncology in the United States.

Surface imaging (SI) has been rapidly integrated into radiotherapy clinics across the country without specific guidelines and recommendations on its commissioning and use aside from vendor-provided information. A survey was created under the auspices of AAPM TG-302 to assess the current status of SI to identify if there is need for formal guidance. The survey was designed to determine the institutional setting of responders, availability and length of its use, commissioning procedures, and clinical applications. This survey was created in REDCap, and approved as IRB exempt to collect anonymized data. Questions were reviewed by multiple physicists to ensure concept validity and piloted by a small group of independent physicists to ensure process validity. All full members of AAPM self-identified as "therapy" or "other" were sent the survey link by email. The survey was active from February to March 2018. Of 3677 members successfully contacted, 439 completed responses; the summary of these responses provides insight on current surface imaging clinical practices, though they should not be assumed to be representative of radiation oncology as a whole. Results showed that 53.3% of respondents have SI in their clinics, mostly in treatment rooms, rarely in simulation rooms. Half of those without SI plan on purchasing it within 3 years. Over 10% have SI but do not use it clinically, 36.8% classify themselves as "expert" users, and 85.5% agreed/strongly agreed that SI guidelines are needed. Initial positioning with SI is most common for breast/chestwall and SRS/SBRT treatments, least common for pediatrics. Use of SI for intra-fraction monitoring follows a similar distribution. Gating with SI is most prevalent for breast/chestwall (66.0%) but also used in SBRT (33.0%), and non-SBRT lung/abdomen (<30%) treatments. SI is a rapidly growing technology in the field with widespread use for several anatomic sites. Guidelines and recommendations on commissioning and clinical use are warranted.

Single-institution report of setup margins of voluntary deep-inspiration breath-hold (DIBH) whole breast radiotherapy implemented with real-time surface imaging.

PURPOSE: We calculated setup margins for whole breast radiotherapy during voluntary deep-inspiration breath-hold (vDIBH) using real-time surface imaging (SI). METHODS AND MATERIALS: Patients (n = 58) with a 27-to-31 split between right- and left-sided cancers were analyzed. Treatment beams were gated using AlignRT by registering the whole breast region-of-interest to the surface generated from the simulation CT scan. AlignRT recorded (three-dimensional) 3D displacements and the beam-on-state every 0.3 s. Means and standard deviations of the displacements during vDIBH for each fraction were used to calculate setup margins. Intra-DIBH stability and the intrafraction reproducibility were estimated from the medians of the 5th to 95th percentile range of the translations in each breath-hold and fraction, respectively. RESULTS: A total of 7269 breath-holds were detected over 1305 fractions in which a median dose of 200 cGy was delivered. Each fraction was monitored for 5.95 ± 2.44 min. Calculated setup margins were 4.8 mm (A/P), 4.9 mm (S/I), and 6.4 mm (L/R). The intra-DIBH stability and the intrafraction reproducibility were ≤0.7 mm and ≤2.2 mm, respectively. The isotropic margin according to SI (9.2 mm) was comparable to other institutions' calculations that relied on x-ray imaging and/or spirometry for patients with left-sided cancer (9.8-11.0 mm). Likewise, intra-DIBH variability and intrafraction reproducibility of breast surface measured with SI agreed with spirometry-based positioning to within 1.2 and 0.36 mm, respectively. CONCLUSIONS: We demonstrated that intra-DIBH variability, intrafraction reproducibility, and setup margins are similar to those reported by peer studies who utilized spirometry-based positioning.

Simultaneously integrated boost (SIB) spares OAR and reduces treatment time in locally advanced cervical cancer.

We performed a dosimetric comparison of sequential IMRT (sIMRT) and simul-taneously integrated boost (SIB) IMRT to boost PET-avid lymph nodes while concurrently treating pelvic targets to determine the potential of SIB IMRT to reduce overall treatment duration in locally advanced cervical cancer. Ten patients receiving definitive radiation therapy were identified retrospectively. RTOG consensus guidelines were followed to delineate the clinical target volume and organs at risk (OAR), which were then expanded per IMRT consortium guidelines to yield the planning target volume (PTV). Dosimetric parameters for PTVs and OAR including conformity (CI95%) were collected and compared using Wilcoxon signed-rank tests with Bonferroni correction. The median PTV volume was 1843 cc (1088-2225 cc) and the median boost volume was 43 cc (15-129 cc). Comparable target volume coverage was achieved with sIMRT and SIB plans, while hot spots were significantly reduced using SIB. SIB plans improved sparing for all OAR, though only rectum and small bowel doses were statistically significant. Comparing sIMRT and SIB plans averaged over all patients, rectal doses were V45: 70.8% vs. 64.5% (p = 0.002) and 0.1 cc: 50.7 Gy vs. 48.7 Gy (p = 0.006). For small bowel, sIMRT and SIB IMRT plans yielded V45: 13.4% vs. 11.4% (p = 0.006) and 1 cc: 54.4 Gy vs. 52.6 Gy (p = 0.006), respectively. Doses to femoral heads and blad-der trended towards significance in favor of SIB plans. The mean treatment time was 25 versus 29 days for SIB and sIMRT plans, respectively. When compared to sIMRT, SIB for treatment of nodal targets provides a significant, but small, dose reduction (3.8%-4.4%) to OAR, which leads to comparable biological dose despite higher fractional doses. Furthermore, SIB IMRT reduces overall treatment time and simplifies the planning process, and should be considered for targeting PET-positive nodal disease in patients with locally advanced cervical cancer.

Comparison of Two Deformable Registration Algorithms in the Presence of Radiologic Change Between Serial Lung CT Scans.

We evaluated the image registration accuracy achieved using two deformable registration algorithms when radiation-induced normal tissue changes were present between serial computed tomography (CT) scans. Two thoracic CT scans were collected for each of 24 patients who underwent radiation therapy (RT) treatment for lung cancer, eight of whom experienced radiologically evident normal tissue damage between pre- and post-RT scan acquisition. For each patient, 100 landmark point pairs were manually placed in anatomically corresponding locations between each pre- and post-RT scan. Each post-RT scan was then registered to the pre-RT scan using (1) the Plastimatch demons algorithm and (2) the Fraunhofer MEVIS algorithm. The registration accuracy for each scan pair was evaluated by comparing the distance between landmark points that were manually placed in the post-RT scans and points that were automatically mapped from pre- to post-RT scans using the displacement vector fields output by the two registration algorithms. For both algorithms, the registration accuracy was significantly decreased when normal tissue damage was present in the post-RT scan. Using the Plastimatch algorithm, registration accuracy was 2.4 mm, on average, in the absence of radiation-induced damage and 4.6 mm, on average, in the presence of damage. When the Fraunhofer MEVIS algorithm was instead used, registration errors decreased to 1.3 mm, on average, in the absence of damage and 2.5 mm, on average, when damage was present. This work demonstrated that the presence of lung tissue changes introduced following RT treatment for lung cancer can significantly decrease the registration accuracy achieved using deformable registration.

Effect of RTOG breast/chest wall guidelines on dose-volume histogram parameters.

Treatment planning for breast cancer has been traditionally based on clinical landmarks. The Radiation Therapy Oncology Group (RTOG) published consensus guidelines on contouring target volumes (TV) for the breast/chest wall and draining lymphatics. The effect of these guidelines on dosimetric parameters in surrounding organs at risk (OAR) and TVs is unknown. Fourteen patients treated with clinically derived plans from 2007-2011 (Group I) and fourteen patients treated with target volume-based plans from 2011-2012 were selected for comparison (Group II). Treatment plans were constructed based on clinical landmarks (Group I) or TVs (Group II) to a median dose of 50.4 Gy to the breast/chest wall, axilla (Ax), supraclavicular (SCV), and internal mammary (IMN) lymph nodes. The RTOG TVs were then contoured in Group I patients by a single investigator blinded to the dose distributions. Dose-volume histograms (DVH) were computed for the RTOG TVs and OARs in both groups, and DVH parameters were compared. In Group II, coverage improved for the SCV (V90 = 78.0% versus 93.6%, p = 0.02) and intact breast (V95 = 95.6% versus 99.3%, p = 0.007). The dose to the cord, the lung (V20Gy and V30Gy), and contralateral breast (V5Gy) were the same. Finally, the low dose to the heart and lung was decreased in Group II (heart V5Gy= 48.7% versus 27.3%, p= 0.02, heart V10Gy = 33.5% vs. 17.5%, p = 0.01, and ipsilateral lung V5Gy = 84.5% vs. 69.3%, p = 0.001). Overall, our study supports that treatment planning using the RTOG consensus guidelines can improve coverage to certain target volumes compared to treatments based solely on clinical landmarks. Additionally, treatment planning using these target volumes does not increase dose to the contralateral breast, cord, heart, or lungs. Longer follow-up is needed to determine if using these target volumes will affect clinical outcomes.

NRG Oncology Assessment of Artificial Intelligence Deep Learning-Based Auto-segmentation for Radiation Therapy: Current Developments, Clinical Considerations, and Future Directions.

Deep learning neural networks (DLNN) in Artificial intelligence (AI) have been extensively explored for automatic segmentation in radiotherapy (RT). In contrast to traditional model-based methods, data-driven AI-based models for auto-segmentation have shown high accuracy in early studies in research settings and controlled environment (single institution). Vendor-provided commercial AI models are made available as part of the integrated treatment planning system (TPS) or as a stand-alone tool that provides streamlined workflow interacting with the main TPS. These commercial tools have drawn clinics' attention thanks to their significant benefit in reducing the workload from manual contouring and shortening the duration of treatment planning. However, challenges occur when applying these commercial AI-based segmentation models to diverse clinical scenarios, particularly in uncontrolled environments. Contouring nomenclature and guideline standardization has been the main task undertaken by the NRG Oncology. AI auto-segmentation holds the potential clinical trial participants to reduce interobserver variations, nomenclature non-compliance, and contouring guideline deviations. Meanwhile, trial reviewers could use AI tools to verify contour accuracy and compliance of those submitted datasets. In recognizing the growing clinical utilization and potential of these commercial AI auto-segmentation tools, NRG Oncology has formed a working group to evaluate the clinical utilization and potential of commercial AI auto-segmentation tools. The group will assess in-house and commercially available AI models, evaluation metrics, clinical challenges, and limitations, as well as future developments in addressing these challenges. General recommendations are made in terms of the implementation of these commercial AI models, as well as precautions in recognizing the challenges and limitations.

Classification of breast lesions pre-contrast injection using water resonance lineshape analysis.

Inhomogeneously broadened, non-Lorentzian water resonances have been observed in small image voxels of breast tissue. The non-Lorentzian components of the water resonance are probably produced by bulk magnetic susceptibility shifts caused by dense, deoxygenated tumor blood vessels (the 'blood oxygenation level-dependent' effect), but can also be produced by other characteristics of local anatomy and physiology, including calcifications and interfaces between different types of tissue. Here, we tested the hypothesis that the detection of non-Lorentzian components of the water resonance with high spectral and spatial resolution (HiSS) MRI allows the classification of breast lesions without the need to inject contrast agent. Eighteen malignant lesions and nine benign lesions were imaged with HiSS MRI at 1.5 T. A new algorithm was developed to detect non-Lorentzian (or off-peak) components of the water resonance. After a Lorentzian fit had been subtracted from the data, the largest peak in the residual spectrum in each voxel was identified as the major off-peak component of the water resonance. The difference in frequency between these off-peak components and the main water peaks, and their amplitudes, were measured in malignant lesions, benign lesions and breast fibroglandular tissue. Off-peak component frequencies were significantly different between malignant and benign lesions (p < 0.001). Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of HiSS off-peak component analysis compared with dynamic contrast-enhanced (DCE) MRI parameters. The areas under the ROC curves for the 'DCE rapid uptake fraction', 'DCE washout fraction', 'off-peak component amplitude' and 'off-peak component frequency' were 0.75, 0.83, 0.50 and 0.86, respectively. These results suggest that water resonance lineshape analysis performs well in the classification of breast lesions without contrast injection and could improve the diagnostic accuracy of clinical breast MR examinations. In addition, this approach may provide an alternative to DCE MRI in women who are at risk for adverse reactions to contrast media.

Improvements in dose accuracy delivered with static-MLC IMRT on an integrated linear accelerator control system.

PURPOSE: Dose accuracy has been shown to vary with dose per segment and dose rate when delivered with static multileaf collimator (SMLC) intensity modulated radiation therapy (IMRT) by Varian C-series MLC controllers. The authors investigated the impact of monitor units (MUs) per segment and dose rate on the dose delivery accuracy of SMLC-IMRT fields on a Varian TrueBeam linear accelerator (LINAC), which delivers dose and manages motion of all components using a single integrated controller. METHODS: An SMLC sequence was created consisting of ten identical 10 × 10 cm(2) segments with identical MUs. Beam holding between segments was achieved by moving one out-of-field MLC leaf pair. Measurements were repeated for various combinations of MU/segment ranging from 1 to 40 and dose rates of 100-600 MU/min for a 6 MV photon beam (6X) and dose rates of 800-2400 MU/min for a 10 MV flattening-filter free photon (10XFFF) beam. All measurements were made with a Farmer (0.6 cm(3)) ionization chamber placed at the isocenter in a solid-water phantom at 10 cm depth. The measurements were performed on two Varian LINACs: C-series Trilogy and TrueBeam. Each sequence was delivered three times and the dose readings for the corresponding segments were averaged. The effects of MU/segment, dose rate, and LINAC type on the relative dose variation (Δ(i)) were compared using F-tests (α = 0.05). RESULTS: On the Trilogy, large Δ(i) was observed in small MU segments: at 1 MU/segment, the maximum Δ(i) was 10.1% and 57.9% at 100 MU/min and 600 MU/min, respectively. Also, the first segment of each sequence consistently overshot (Δ(i) > 0), while the last segment consistently undershot (Δ(i) < 0). On the TrueBeam, at 1 MU/segment, Δ(i) ranged from 3.0% to 4.5% at 100 and 600 MU/min; no obvious overshoot/undershoot trend was observed. F-tests showed statistically significant difference [(1 - ß) =1.0000] between the Trilogy and the TrueBeam up to 10 MU/segment, at all dose rates greater than 100 MU/min. The linear trend of decreasing dose accuracy as a function of increasing dose rate on the Trilogy is no longer apparent on TrueBeam, even for dose rates as high as 2400 MU/min. Dose inaccuracy averaged over all ten segments in each beam delivery sequence was larger for Trilogy than TrueBeam, with the largest discrepancy (0.2% vs 3%) occurring for 1 MU/segment beams at both 300 and 600 MU/min. CONCLUSIONS: Earlier generations of Varian LINACs exhibited large dose variations for small MU segments in SMLC-IMRT delivery. Our results confirmed these findings. The dose delivery accuracy for SMLC-IMRT is significantly improved on TrueBeam compared to Trilogy for every combination of low MU/segment (1-10) and high dose rate (200-600 MU/min), in part due to the faster sampling rate (100 vs 20 Hz) and enhanced electronic integration of the MLC controller with the LINAC. SMLC-IMRT can be implemented on TrueBeam with higher dose accuracy per beam (±0.2% vs ±3%) than previous generations of Varian C-series LINACs for 1 MU/segment delivered at 600 MU/min).

Lung texture in serial thoracic CT scans: assessment of change introduced by image registration.

PURPOSE: The aim of this study was to quantify the effect of four image registration methods on lung texture features extracted from serial computed tomography (CT) scans obtained from healthy human subjects. METHODS: Two chest CT scans acquired at different time points were collected retrospectively for each of 27 patients. Following automated lung segmentation, each follow-up CT scan was registered to the baseline scan using four algorithms: (1) rigid, (2) affine, (3) B-splines deformable, and (4) demons deformable. The registration accuracy for each scan pair was evaluated by measuring the Euclidean distance between 150 identified landmarks. On average, 1432 spatially matched 32 × 32-pixel region-of-interest (ROI) pairs were automatically extracted from each scan pair. First-order, fractal, Fourier, Laws' filter, and gray-level co-occurrence matrix texture features were calculated in each ROI, for a total of 140 features. Agreement between baseline and follow-up scan ROI feature values was assessed by Bland-Altman analysis for each feature; the range spanned by the 95% limits of agreement of feature value differences was calculated and normalized by the average feature value to obtain the normalized range of agreement (nRoA). Features with small nRoA were considered "registration-stable." The normalized bias for each feature was calculated from the feature value differences between baseline and follow-up scans averaged across all ROIs in every patient. Because patients had "normal" chest CT scans, minimal change in texture feature values between scan pairs was anticipated, with the expectation of small bias and narrow limits of agreement. RESULTS: Registration with demons reduced the Euclidean distance between landmarks such that only 9% of landmarks were separated by ≥1 mm, compared with rigid (98%), affine (95%), and B-splines (90%). Ninety-nine of the 140 (71%) features analyzed yielded nRoA > 50% for all registration methods, indicating that the majority of feature values were perturbed following registration. Nineteen of the features (14%) had nRoA < 15% following demons registration, indicating relative feature value stability. Student's t-tests showed that the nRoA of these 19 features was significantly larger when rigid, affine, or B-splines registration methods were used compared with demons registration. Demons registration yielded greater normalized bias in feature value change than B-splines registration, though this difference was not significant (p = 0.15). CONCLUSIONS: Demons registration provided higher spatial accuracy between matched anatomic landmarks in serial CT scans than rigid, affine, or B-splines algorithms. Texture feature changes calculated in healthy lung tissue from serial CT scans were smaller following demons registration compared with all other algorithms. Though registration altered the values of the majority of texture features, 19 features remained relatively stable after demons registration, indicating their potential for detecting pathologic change in serial CT scans. Combined use of accurate deformable registration using demons and texture analysis may allow for quantitative evaluation of local changes in lung tissue due to disease progression or treatment response.

Evaluation of Dose Distribution to Organs-at-Risk in a Prospective Phase 1 Trial of Pembrolizumab and Multisite Stereotactic Body Radiation Therapy (SBRT).

PURPOSE: Our purpose was to characterize the radiation doses to organs-at-risk (OAR) in the phase I trial (NCT02608385) that established safety/efficacy of stereotactic body radiation therapy (SBRT) using NRG-BR001 dose constraints combined with programmed cell death protein 1 blockade for metastatic disease. METHODS AND MATERIALS: Between January 2016 and May 2018, 73 patients with advanced solid tumors were treated with SBRT followed by pembrolizumab. Tumor volumes (gross tumor volume/internal tumor volume) were delineated for each metastasis, with planning target volume contraction to limit OAR dose per protocol (n = 54) or when gross tumor volume/internal tumor volume > 65 cm3 (n = 19). For 20 OAR, doses were compared with NRG-BR001 constraints. Protocol constraints were considered challenged when the minimum of the highest dose received by ≥6 patients without dose-limiting toxicities (DLTs) (Dmax6th) was ≥70% of the protocol constraint. RESULTS: A total of 151 metastases were irradiated including 32 peripheral lung, 23 central lung, 13 mediastinal/cervical, 24 liver, 28 abdominal-pelvic, 16 osseous, and 15 spinal metastases. A median of 2 metastases (range, 2-4) with mean volumes of 33.5 cm3 (range, 0.4-391 cm3) were treated using average planning target volumes of 50.7 cm3 (range, 3.2-161 cm3). At least 1 dose constraint from NRG-BR001 was exceeded in 38 of 73 (52%) patients. OAR constraints were challenged in 10 serial organs (gastrointestinal, cardio-pulmonary, musculoskeletal, and nervous systems) and 1 parallel OAR (lung). Grade 3 DLTs occurred in 6 patients, including pneumonitis (n = 3), colitis (n = 2), and hepatic failure (n = 1). In 4 patients, the toxicity could be directly attributed to the planned dose to OAR (ie, pneumonitis due to high lung dose or colitis due to high bowel dose). CONCLUSIONS: Multisite SBRT in combination with programmed cell death protein 1 blockade was safely tolerated when treating critical central, abdominal-pelvic, and peripheral OAR nearing NRG-BR001 constraints with clinically acceptable toxicity in the corresponding organ systems. The observed relationship between dose and DLTs in 4 of 6 patients indicates that NRG-BR001 dose constraints should be respected in subsequent trials to maintain clinical safety.

AAPM task group report 302: Surface-guided radiotherapy.

The clinical use of surface imaging has increased dramatically, with demonstrated utility for initial patient positioning, real-time motion monitoring, and beam gating in a variety of anatomical sites. The Therapy Physics Subcommittee and the Imaging for Treatment Verification Working Group of the American Association of Physicists in Medicine commissioned Task Group 302 to review the current clinical uses of surface imaging and emerging clinical applications. The specific charge of this task group was to provide technical guidelines for clinical indications of use for general positioning, breast deep-inspiration breath hold treatment, and frameless stereotactic radiosurgery. Additionally, the task group was charged with providing commissioning and on-going quality assurance (QA) requirements for surface-guided radiation therapy (SGRT) as part of a comprehensive QA program including risk assessment. Workflow considerations for other anatomic sites and for computed tomography simulation, including motion management, are also discussed. Finally, developing clinical applications, such as stereotactic body radiotherapy (SBRT) or proton radiotherapy, are presented. The recommendations made in this report, which are summarized at the end of the report, are applicable to all video-based SGRT systems available at the time of writing.

Development of a neonate X-ray phantom for 2D imaging applications using single-tone inkjet printing.

PURPOSE: Inkjet printers can be used to fabricate anthropomorphic phantoms by the use of iodine-doped ink. However, challenges persist in implementing this technique. The calibration from grayscale to ink density is complex and time-consuming. The purpose of this work is to develop a printing methodology that requires a simpler calibration and is less dependent on printer characteristics to produce the desired range of x-ray attenuation values. METHODS: Conventional grayscale printing was substituted by single-tone printing; that is, the superposition of pure black layers of iodinated ink. Printing was performed with a consumer-grade inkjet printer using ink made of potassium-iodide (KI) dissolved in water at 1 g/ml. A calibration for the attenuation of ink was measured using a commercial x-ray system at 70 kVp. A neonate radiograph obtained at 70 kVp served as an anatomical model. The attenuation map of the neonate radiograph was processed into a series of single-tone images. Single-tone images were printed, stacked, and imaged at 70 kVp. The phantom was evaluated by comparing attenuation values between the printed phantom and the original radiograph; attenuation maps were compared using the structural similarity index measure (SSIM), while attenuation histograms were compared using the Kullback-Leibler (KL) divergence. A region of interest (ROI)-based analysis was also performed, where the attenuation distribution within given ROIs was compared between phantom and patient. The phantom sharpness was evaluated in terms of modulation transfer function (MTF) estimates and signal spread profiles of high spatial resolution features in the image. RESULTS: The printed phantom required 36 pages. The printing queue was automated and it took about 2 h to print the phantom. The radiograph of the printed phantom demonstrated a close resemblance to the original neonate radiograph. The SSIM of the phantom with respect to that of the patient was 0.53. Both patient and phantom attenuation histograms followed similar distributions, and the KL divergence between such histograms was 0.20. The ROI-based analysis showed that the largest deviations from patient attenuation values were observed at the higher and lower ends of the attenuation range. The limiting resolution of the proposed methodology was about 1 mm. CONCLUSION: A methodology to generate a neonate phantom for 2D imaging applications, using single-tone printing, was developed. This method only requires a single-value calibration and required less than 2 h to print a complete phantom.

Effects of variability in radiomics software packages on classifying patients with radiation pneumonitis.

Purpose: While radiomics feature values can differ when extracted using different radiomics software, the effects of these variations when applied to a particular clinical task are currently unknown. The goal of our study was to use various radiomics software packages to classify patients with radiation pneumonitis (RP) and to quantify the variation in classification ability among packages. Approach: A database of serial thoracic computed tomography scans was obtained from 105 patients with esophageal cancer. Patients were treated with radiation therapy (RT), resulting in 20 patients developing RP grade ≥ 2 . Regions of interest (ROIs) were randomly placed in the lung volume of the pre-RT scan within high-dose regions ( ≥ 30 Gy ), and corresponding ROIs were anatomically matched in the post-RT scan. Three radiomics packages were compared: A1 (in-house), IBEX v1.0 beta, and PyRadiomics v.2.0.0. Radiomics features robust to deformable registration and common among radiomics packages were calculated: four first-order and four gray-level co-occurrence matrix features. Differences in feature values between time points were calculated for each feature, and logistic regression was used in conjunction with analysis of variance to classify patients with and without RP ( p < 0.006 ). Classification ability for each package was assessed using receiver operating characteristic (ROC) analysis and compared using the area under the ROC curve (AUC). Results: Of the eight radiomics features, five were significantly correlated with RP status for all three packages, whereas one feature was not significantly correlated with RP for all three packages. The remaining two features differed in whether or not they were significantly associated with RP status among the packages. Seven of the eight features agreed among the packages in whether the AUC value was significantly > 0.5 . Conclusions: Radiomics features extracted using different software packages can result in differences in classification ability.

Interstitial High-Dose-Rate Gynecologic Brachytherapy: Clinical Workflow Experience From Three Academic Institutions.

An interstitial brachytherapy approach for gynecologic cancers is typically considered for patients with lesions exceeding 5 mm within tissue or that are not easily accessible for intracavitary applications. Recommendations for treating gynecologic malignancies with this approach are available through the American Brachytherapy Society, but vary based on available resources, staffing, and logistics. The intent of this manuscript is to share the collective experience of 3 academic centers that routinely perform interstitial gynecologic brachytherapy. Discussion points include indications for interstitial implants, procedural preparations, applicator selection, anesthetic options, imaging, treatment planning objectives, clinical workflows, timelines, safety, and potential challenges. Interstitial brachytherapy is a complex, high-skill procedure requiring routine practice to optimize patient safety and treatment efficacy. Clinics planning to implement this approach into their brachytherapy practice may benefit from considering the discussion points shared in this manuscript.

Harmonization of radiomic feature variability resulting from differences in CT image acquisition and reconstruction: assessment in a cadaveric liver.

Studies investigating the effects of computed tomography (CT) image acquisition and reconstruction parameters have mostly been limited to non-human phantoms to limit exposure to patients. This study investigates these variations using a cadaveric liver and determines harmonization methods to mitigate these variations. A reference CT scan of a cadaveric liver was acquired along with 16 modified scans. Modified scans were obtained with altered image acquisition and reconstruction parameters. In each slice, the liver was segmented and used to calculate 142 features. Student's t-tests assessed differences between reference and modified scans for each feature after correcting for multiple comparisons. Features were harmonized between reference and modified scans using histogram normalization, pixel resampling, Butterworth filtering, resampling and filtering combined, and ComBat harmonization. The number of features reflecting significant differences before and after harmonization were compared across imaging parameters. Reducing the field-of-view (FOV) and using coronal instead of axial scans resulted in the greatest number of features reflecting significant differences (67.6%, and 35.9%, respectively) and resulted in the greatest median relative change in feature values (25.4% and 18.2%, respectively). Changes in tube voltage, pitch, and slice interval resulted in the smallest number of features reflecting significance (0.7%) with median relative changes in feature <2%. Histogram normalization reduced or maintained the number of significantly different features for all scans, while ComBat reduced the number of significantly different features to zero for all scans. The remaining harmonization methods had mixed effects: resampling reduced the number of features reflecting significant differences for half of the imaging parameters, while filtering alone and filtering combined with resampling both reduced the number of features reflecting significance for 10 of the 16 parameters. The dependence of radiomic features on image acquisition and reconstruction parameters varies in a cadaveric liver; however, various harmonization methods have shown promise in mitigating these dependencies, particularly ComBat.

Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors.

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ-induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ-associated genes from post-SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1-directed immunotherapy are warranted.

Incorporation of pre-therapy 18 F-FDG uptake data with CT texture features into a radiomics model for radiation pneumonitis diagnosis.

PURPOSE: To determine whether the addition of standardized uptake value (SUV) from PET scans to CT lung texture features could improve a radiomics-based model of radiation pneumonitis (RP) diagnosis in patients undergoing radiotherapy. METHODS AND MATERIALS: Anonymized data from 96 esophageal cancer patients (18 RP-positive cases of Grade ≥ 2) were collected including pre-therapy PET/CT scans, pre-/post-therapy diagnostic CT scans and RP status. Twenty texture features (first-order, fractal, Laws' filter and gray-level co-occurrence matrix) were calculated from diagnostic CT scans and compared in anatomically matched regions of the lung. Classifier performance (texture, SUV, or combination) was assessed by calculating the area under the receiver operating characteristic curve (AUC). For each texture feature, logistic regression classifiers consisting of the average change in texture feature value and the pre-therapy SUV standard deviation (SUVSD ) were created and compared with the texture feature as a lone classifier using ANOVA with correction for multiple comparisons (P < 0.0025). RESULTS: While clinical parameters (mean lung dose, smoking history, tumor location) were not significantly different among patients with and without symptomatic RP, SUV and texture parameters were significantly associated with RP status. AUC for single-texture feature classifiers alone ranged from 0.58 to 0.81 and 0.53 to 0.71 in high-dose (≥ 30 Gy) and low-dose (< 10 Gy) regions of the lungs, respectively. AUC for SUVSD alone was 0.69 (95% confidence interval: 0.54-0.83). Adding SUVSD into a logistic regression model significantly improved model fit for 18, 14 and 11 texture features and increased the mean AUC across features by 0.08, 0.06, and 0.04 in the low-, medium-, and high-dose regions, respectively. CONCLUSIONS: Addition of SUVSD to a single-texture feature improves classifier performance on average, but the improvement is smaller in magnitude when SUVSD is added to an already effective classifier using texture alone. These findings demonstrate the potential for more accurate assessment of RP using information from multiple imaging modalities.

Benchmark Credentialing Results for NRG-BR001: The First National Cancer Institute-Sponsored Trial of Stereotactic Body Radiation Therapy for Multiple Metastases.

PURPOSE: The NRG-BR001 trial is the first National Cancer Institute-sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. METHODS AND MATERIALS: The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by <5 cm of normal tissue. Because the planning target volume (PTV) overlaps with organs at risk (OARs), institutions must use the planning priority guidelines to balance PTV coverage (45 Gy in 3 fractions) against OAR sparing. Submitted plans were processed by the Imaging and Radiation Oncology Core and assessed by the protocol co-chairs by comparing the doses to targets, OARs, and conformity metrics using nonparametric tests. RESULTS: Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm3 was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. CONCLUSIONS: Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements.

Rationale of technical requirements for NRG-BR001: The first NCI-sponsored trial of SBRT for the treatment of multiple metastases.

INTRODUCTION: In 2014, the NRG Oncology Group initiated the first National Cancer Institute-sponsored, phase 1 clinical trial of stereotactic body radiation therapy (SBRT) for the treatment of multiple metastases in multiple organ sites (BR001; NCT02206334). The primary endpoint is to test the safety of SBRT for the treatment of 2 to 4 multiple lesions in several anatomic sites in a multi-institutional setting. Because of the technical challenges inherent to treating multiple lesions as their spatial separation decreases, we present the technical requirements for NRG-BR001 and the rationale for their selection. METHODS AND MATERIALS: Patients with controlled primary tumors of breast, non-small cell lung, or prostate are eligible if they have 2 to 4 metastases distributed among 7 extracranial anatomic locations throughout the body. Prescription and organ-at-risk doses were determined by expert consensus. Credentialing requirements include (1) irradiation of the Imaging and Radiation Oncology Core phantom with SBRT, (2) submitting image guided radiation therapy case studies, and (3) planning the benchmark. Guidelines for navigating challenging planning cases including assessing composite dose are discussed. RESULTS: Dosimetric planning to multiple lesions receiving differing doses (45-50 Gy) and fractionation (3-5) while irradiating the same organs at risk is discussed, particularly for metastases in close proximity (≤5 cm). The benchmark case was selected to demonstrate the planning tradeoffs required to satisfy protocol requirements for 2 nearby lesions. Examples of passing benchmark plans exhibited a large variability in plan conformity. DISCUSSION: NRG-BR001 was developed using expert consensus on multiple issues from the dose fractionation regimen to the minimum image guided radiation therapy guidelines. Credentialing was tied to the task rather than the anatomic site to reduce its burden. Every effort was made to include a variety of delivery methods to reflect current SBRT technology. Although some simplifications were adopted, the successful completion of this trial will inform future designs of both national and institutional trials and would allow immediate clinical adoption of SBRT trials for oligometastases.