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.

Purpose To assess the relationship between radiation dose and change in a set of mathematical intensity- and texture-based features and to determine the ability of texture analysis to identify patients who develop radiation pneumonitis (RP). Methods and Materials A total of 106 patients who received radiation therapy (RT) for esophageal cancer were retrospectively identified under institutional review board approval. For each patient, diagnostic computed tomography (CT) scans were acquired before (0–168 days) and after (5–120 days) RT, and a treatment planning CT scan with an associated dose map was obtained. 32- × 32-pixel regions of interest (ROIs) were randomly identified in the lungs of each pre-RT scan. ROIs were subsequently mapped to the post-RT scan and the planning scan dose map by using deformable image registration. The changes in 20 feature values (ΔFV) between pre- and post-RT scan ROIs were calculated. Regression modeling and analysis of variance were used to test the relationships between ΔFV, mean ROI dose, and development of grade ≥2 RP. Area under the receiver operating characteristic curve (AUC) was calculated to determine each feature’s ability to distinguish between patients with and those without RP. A classifier was constructed to determine whether 2- or 3-feature combinations could improve RP distinction. Results For all 20 features, a significant ΔFV was observed with increasing radiation dose. Twelve features changed significantly for patients with RP. Individual texture features could discriminate between patients with and those without RP with moderate performance (AUCs from 0.49 to 0.78). Using multiple features in a classifier, AUC increased significantly (0.59–0.84). Conclusions A relationship between dose and change in a set of image-based features was observed. For 12 features, ΔFV was significantly related to RP development. This study demonstrated the ability of radiomics to provide a quantitative, individualized measurement of patient lung tissue reaction to RT and assess RP development.

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.

The purpose of this study was to quantify the variability of the breast surface position when aligning whole-breast patients to bony landmarks based on MV portal films or skin marks alone. Surface imaging was used to assess the breast surface position of 11 whole-breast radiotherapy patients, but was not used for patient positioning. On filmed fractions, AlignRT v5.0 was used to capture the patient's surface after initial positioning based on skin marks (28 “preshifts” surfaces), and after treatment couch shifts based on MV films (41 “postshifts” surfaces). Translations and rotations based on surface captures were recorded, as well as couch shifts based on MV films. For nonfilmed treatments, “daily” surface images were captured following positioning to skin marks alone. Group mean and systematic and random errors were calculated for all datasets. Pearson correlation coefficients, setup margins, and 95% limits of agreement (LOA) were calculated for preshifts translations and MV film shifts. LOA between postshifts surfaces and the filmed treatment positions were also computed. All the surface captures collected were retrospectively compared to both a DICOM reference surface created from the planning CT and to an AlignRT reference surface. All statistical analyses were performed using the DICOM reference surface dataset. AlignRT reference surface data was only used to calculate the LOA with the DICOM reference data. This helped assess any outcome differences between both reference surfaces. Setup margins for preshifts surfaces and MV films range between 8.3–12.0 mm and 5.4–13.4 mm, respectively. The largest margin is along the left–right (LR) direction for preshift surfaces, and along craniocaudal (CC) for films. LOA ranges between the preshifts surfaces and MV film shifts are large (12.6–21.9 mm); these decrease for postshifts surfaces (9.8–18.4 mm), but still show significant disagreements between the two modalities due to their focus on different anatomical landmarks (patient's topography versus bony anatomy). Pearson's correlation coefficients further support this by showing low to moderate correlations in the anterior–posterior (AP) and LR directions (0.47–0.69) and no correlation along CC (< 0.15). The use of an AlignRT reference surface compared to the DICOM reference surface does not significantly affect the LOA. Alignment of breast patients based solely on bony alignment may lead to interfractional inconsistencies in the breast surface position. The use of surface imaging tools highlights these discrepancies, and allows the radiation oncology team to better assess the possible effects on treatment quality.

Introduction In 2014, the NRG Oncology Group initiated the first NCI-sponsored, phase I clinical trial of SBRT for the treatment of multiple metastases in multiple organ sites (XXXX; NCTXXX). The primary endpoint is to test the safety of SBRT for the treatment of multiple lesions (2–4) 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-XXXX 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 2–4 metastases distributed among 7 extracranial anatomic locations throughout the body. Prescription and organ-at-risk (OAR) doses were determined by expert consensus. Credentialing requirements include 1) irradiation of the IROC phantom with SBRT, 2) submitting IGRT 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 (45–50Gy) and fractionation (3–5) while irradiating the same organs-at-risk is discussed, particularly for metastases in close proximity (≤5cm). The benchmark case was selected to demonstrate the planning trade-offs required to satisfy protocol requirements for two nearby lesions. Examples of passing benchmark plans exhibited a large variability in plan conformity. Discussion NRG-XXXX was developed using expert consensus on multiple issues from the dose fractionation regimen to the minimum IGRT guidelines. Credentialing was tied to the task rather than the anatomic site in order to reduce its burden. Every effort was made to include a variety of delivery methods to reflect current SBRT technology. While some simplifications were adopted, the successful completion of this trial will inform future designs of both national and institutional would allow immediate clinical adoption of SBRT trials for oligometastases.

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MRI detects changes in blood-oxygenation-level dependent (BOLD) contrast in tumors caused by tumor oxygenating agents. These changes can be used to guide the design of improved tumor oxygenating treatments (TOXs). The conventional approach to detection of BOLD effects assumes that the water resonance is a single, homogeneously broadened Lorentzian line, and that changes in the T2* of this line owing to changes in deoxyhemoglobin are spectrally homogeneous. This model may not adequately describe BOLD contrast changes in complex water resonances that are often detected in tumors. The present work investigated: (a) whether changes in the water resonance in very small voxels caused by tumor oxygenating agents are spectrally inhomogeneous; and (b) whether high spectral and spatial resolution (HiSS) MRI of the water and fat resonances detects these changes more accurately than conventional gradient-recalled echo (GRE) imaging. Carbogen (95% oxygen, 5% CO2) was used to increase tumor oxygenation. In two tumor models [mammary adenocarcinoma (R3230Ac; n=5) and rhabdomyosarcoma (BA1112; n=5)] proton signals were often complex and inhomogeneously broadened. Spectrally inhomogeneous changes during carbogen breathing occurred in at least 10% of the R3230AC tumor voxels that responded to carbogen and 18% of BA1112 tumor voxels. The largest changes during carbogen breathing in many voxels occurred at frequencies that were significantly different from the frequency of the primary water peak. Carbogen-induced changes in proton T2* detected by simulated GRE and HiSS differed by more than 75% in 67% of voxels in R3230Ac tumors and in 65% of voxels in BA1112 tumors. The spectrally inhomogeneous effects of tumor oxygenating agents may reflect changes in sub-voxelar microenvironements and thus may be important for accurate evaluation of the effects of therapy.

Given the increased need for consistent quantitative image analysis, variations in radiomics feature calculations due to differences in radiomics software were investigated. Two in-house radiomics packages and two freely available radiomics packages, MaZda and IBEX, were utilized. Forty 256 × 256-pixel regions of interest (ROIs) from 40 digital mammograms were studied along with 39 manually delineated ROIs from the head and neck (HN) computed tomography (CT) scans of 39 patients. Each package was used to calculate first-order histogram and second-order gray-level co-occurrence matrix (GLCM) features. Friedman tests determined differences in feature values across packages, whereas intraclass-correlation coefficients (ICC) quantified agreement. All first-order features computed from both mammography and HN cases (except skewness in mammography) showed significant differences across all packages due to systematic biases introduced by each package; however, based on ICC values, all but one first-order feature calculated on mammography ROIs and all but two first-order features calculated on HN CT ROIs showed excellent agreement, indicating the observed differences were small relative to the feature values but the bias was systematic. All second-order features computed from the two databases both differed significantly and showed poor agreement among packages, due largely to discrepancies in package-specific default GLCM parameters. Additional differences in radiomics features were traced to variations in image preprocessing, algorithm implementation, and naming conventions. Large variations in features among software packages indicate that increased efforts to standardize radiomics processes must be conducted. © The Authors. Published by SPIE and CLP under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.