Biochemical Relapse-Free Survival in Postprostatectomy Patients Receiving 18F-Fluciclovine-Guided Prostate Bed-Only Radiation: Post Hoc Analysis of a Prospective Randomized Trial.

PURPOSE: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance. METHODS AND MATERIALS: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate. RESULTS: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01. CONCLUSIONS: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes.

The Utility of Spectroscopic MRI in Stereotactic Biopsy and Radiotherapy Guidance in Newly Diagnosed Glioblastoma.

Current diagnostic and therapeutic approaches for gliomas have limitations hindering survival outcomes. We propose spectroscopic magnetic resonance imaging as an adjunct to standard MRI to bridge these gaps. Spectroscopic MRI is a volumetric MRI technique capable of identifying tumor infiltration based on its elevated choline (Cho) and decreased N-acetylaspartate (NAA). We present the clinical translatability of spectroscopic imaging with a Cho/NAA ≥ 5x threshold for delineating a biopsy target in a patient diagnosed with non-enhancing glioma. Then, we describe the relationship between the undertreated tumor detected with metabolite imaging and overall survival (OS) from a pilot study of newly diagnosed GBM patients treated with belinostat and chemoradiation. Each cohort (control and belinostat) were split into subgroups using the median difference between pre-radiotherapy Cho/NAA ≥ 2x and the treated T1-weighted contrast-enhanced (T1w-CE) volume. We used the Kaplan-Meier estimator to calculate median OS for each subgroup. The median OS was 14.4 months when the difference between Cho/NAA ≥ 2x and T1w-CE volumes was higher than the median compared with 34.3 months when this difference was lower than the median. The T1w-CE volumes were similar in both subgroups. We find that patients who had lower volumes of undertreated tumors detected via spectroscopy had better survival outcomes.

Implementation of a Novel Chart Rounds Application to Facilitate Peer Review in a Virtual Academic Environment.

Purpose: Peer review in the form of chart rounds is a critical component of quality assurance and safety in radiation therapy treatments. Radiation therapy departments have undergone significant changes that impose challenges to meaningful review, including institutional growth and increasing use of virtual environment. We discuss the implementation of a novel chart rounds (NCR) format and application adapted to modern peer review needs at a single high-volume multisite National Cancer Institute designated cancer center. Methods and Materials: A working group was created to improve upon the prior institutional chart rounds format (standard chart rounds or SCR). Using a novel in-house application and format redesign, an NCR was created and implemented to accomplish stated goals. Data regarding the SCR and NCR system were then extracted for review. Results: SCR consisted of 2- 90-minute weekly sessions held to review plans across all disease sites, review of 49 plans per hour on average. NCR uses 1-hour long sessions divided by disease site, enabling additional time to be spent per patient (11 plans per hour on average) and more robust discussion. The NCR application is able to automate a list of plans requiring peer review from the institutional treatment planning system. The novel application incorporates features that enable efficient and accurate review of plans in the virtual setting across multiple sites. A systematic scoring system is integrated into the application to record feedback. Over 5 months of use of the NCR, 1160 plans have been reviewed with 143 scored as requiring minor changes, 32 requiring major changes and 307 with comments. Major changes triggered treatment replan. Feedback from scoring is incorporated into physician workflow to ensure changes are addressed. Conclusion: The presented NCR format and application enables standardized and highly reliable peer review of radiation therapy plans that is robust across a variety of complex planning scenarios and could be implemented globally.

Total scalp irradiation: A study comparing multiple types of bolus and VMAT optimization techniques.

PURPOSE: To investigate bolus design and VMAT optimization settings for total scalp irradiation. METHODS: Three silicone bolus designs (flat, hat, and custom) from .decimal were evaluated for adherence to five anthropomorphic head phantoms. Flat bolus was cut from a silicone sheet. Generic hat bolus resembles an elongated swim cap while custom bolus is manufactured by injecting silicone into a 3D printed mold. Bolus placement time was recorded. Air gaps between bolus and scalp were quantified on CT images. The dosimetric effect of air gaps on target coverage was evaluated in a treatment planning study where the scalp was planned to 60 Gy in 30 fractions. A noncoplanar VMAT technique based on gEUD penalties was investigated that explored the full range of gEUD alpha values to determine which settings achieve sufficient target coverage while minimizing brain dose. ANOVA and the t-test were used to evaluate statistically significant differences (threshold = 0.05). RESULTS: The flat bolus took 32 ± 5.9 min to construct and place, which was significantly longer (p < 0.001) compared with 0.67 ± 0.2 min for the generic hat bolus or 0.53 ± 0.10 min for the custom bolus. The air gap volumes were 38 ± 9.3 cc, 32 ± 14 cc, and 17 ± 7.0 cc for the flat, hat, and custom boluses, respectively. While the air gap differences between the flat and custom boluses were significant (p = 0.011), there were no significant dosimetric differences in PTV coverage at V57Gy or V60Gy. In the VMAT optimization study, a gEUD alpha of 2 was found to minimize the mean brain dose. CONCLUSIONS: Two challenging aspects of total scalp irradiation were investigated: bolus design and plan optimization. Results from this study show opportunities to shorten bolus fabrication time during simulation and create high quality treatment plans using a straightforward VMAT template with simple optimization settings.

Lesion segmentation on 18F-fluciclovine PET/CT images using deep learning.

Background and purpose: A novel radiotracer, 18F-fluciclovine (anti-3-18F-FACBC), has been demonstrated to be associated with significantly improved survival when it is used in PET/CT imaging to guide postprostatectomy salvage radiotherapy for prostate cancer. We aimed to investigate the feasibility of using a deep learning method to automatically detect and segment lesions on 18F-fluciclovine PET/CT images. Materials and methods: We retrospectively identified 84 patients who are enrolled in Arm B of the Emory Molecular Prostate Imaging for Radiotherapy Enhancement (EMPIRE-1) trial. All 84 patients had prostate adenocarcinoma and underwent prostatectomy and 18F-fluciclovine PET/CT imaging with lesions identified and delineated by physicians. Three different neural networks with increasing levels of complexity (U-net, Cascaded U-net, and a cascaded detection segmentation network) were trained and tested on the 84 patients with a fivefold cross-validation strategy and a hold-out test, using manual contours as the ground truth. We also investigated using both PET and CT or using PET only as input to the neural network. Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (HD95), center-of-mass distance (CMD), and volume difference (VD) were used to quantify the quality of segmentation results against ground truth contours provided by physicians. Results: All three deep learning methods were able to detect 144/155 lesions and 153/155 lesions successfully when PET+CT and PET only, respectively, served as input. Quantitative results demonstrated that the neural network with the best performance was able to segment lesions with an average DSC of 0.68 ± 0.15 and HD95 of 4 ± 2 mm. The center of mass of the segmented contours deviated from physician contours by approximately 2 mm on average, and the volume difference was less than 1 cc. The novel network proposed by us achieves the best performance compared to current networks. The addition of CT as input to the neural network contributed to more cases of failure (DSC = 0), and among those cases of DSC > 0, it was shown to produce no statistically significant difference with the use of only PET as input for our proposed method. Conclusion: Quantitative results demonstrated the feasibility of the deep learning methods in automatically segmenting lesions on 18F-fluciclovine PET/CT images. This indicates the great potential of 18F-fluciclovine PET/CT combined with deep learning for providing a second check in identifying lesions as well as saving time and effort for physicians in contouring.

Applying a Radiation Therapy Volume Analysis Pipeline to Determine the Utility of Spectroscopic MRI-Guided Adaptive Radiation Therapy for Glioblastoma.

Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (p = 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (p = 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning.

A Novel Approach to Determining Tumor Progression Using a Three-Site Pilot Clinical Trial of Spectroscopic MRI-Guided Radiation Dose Escalation in Glioblastoma.

Glioblastoma (GBM) is a fatal disease, with poor prognosis exacerbated by difficulty in assessing tumor extent with imaging. Spectroscopic MRI (sMRI) is a non-contrast imaging technique measuring endogenous metabolite levels of the brain that can serve as biomarkers for tumor extension. We completed a three-site study to assess survival benefits of GBM patients when treated with escalated radiation dose guided by metabolic abnormalities in sMRI. Escalated radiation led to complex post-treatment imaging, requiring unique approaches to discern tumor progression from radiation-related treatment effect through our quantitative imaging platform. The purpose of this study is to determine true tumor recurrence timepoints for patients in our dose-escalation multisite study using novel methodology and to report on median progression-free survival (PFS). Follow-up imaging for all 30 trial patients were collected, lesion volumes segmented and graphed, and imaging uploaded to our platform for visual interpretation. Eighteen months post-enrollment, the median PFS was 16.6 months with a median time to follow-up of 20.3 months. With this new treatment paradigm, incidence rate of tumor recurrence one year from treatment is 30% compared to 60-70% failure under standard care. Based on the delayed tumor progression and improved survival, a randomized phase II trial is under development (EAF211).

Lung SBRT treatment planning: a study of VMAT arc selection guided by collision check software.

To evaluate the effects of arc geometry on lung stereotactic body radiation therapy (SBRT) plan quality, using collision check software to select safe beam angles. Thirty lung SBRT cases were replanned 10Gy x 5 using 4 volumetric modulated arc therapy (VMAT) geometries: coplanar lateral (cpLAT), coplanar oblique (cpOBL), noncoplanar lateral (ncpLAT) and noncoplanar oblique (ncpOBL). Lateral arcs spanned 180° on the affected side whereas the 180° oblique arcs crossed midline to spare healthy tissues. Couch angles were separated by 30° on noncoplanar plans. Clearance was verified with Radformation CollisionCheck software. Optimization objectives were the same across the four plans for each case. Planning target volume (PTV) coverage was set to 95% and then plans were evaluated for dose conformity, healthy tissue doses, and monitor units. Clinically treated plans were used to benchmark the results. The volumes of the 25%, 50% and 75% isodoses were smaller with noncoplanar than coplanar arcs. The volume of the 50% isodose line relative to the PTV (CI50%) was as follows: clinical 3.75±0.72, cpLAT 3.39 ± 0.37, cpOBL 3.36 ± 0.34, ncpLAT 3.02 ± 0.21 and ncpOBL 3.02 ± 0.22. The Wilcoxon signed rank test with Bonferroni correction showed p < 0.005 in all CI50% comparisons except between the cpLat and cpObl arcs and between the ncpLat and ncpObl arcs. The best lung sparing was achieved using ncpObl arcs, which was statistically significant (p < 0.001) compared with the other four plans at V12.5Gy, V13.5Gy and V20Gy. Chest wall V30Gy was significantly better using noncoplanar arcs in comparison to the other plan types (p < 0.001). The best heart sparing at V10Gy from the ncpOBL arcs was significant compared with the clinical and cpLat plans (p < 0.005). Arc geometry has a substantial effect on lung SBRT plan quality. Noncoplanar arcs were superior to coplanar arcs at compacting the dose distribution at the 25%, 50% and 75% isodose levels, thereby reducing the dose to healthy tissues. Further healthy tissue sparing was achieved using oblique arcs that minimize the pathlength through healthy tissues and avoid organs at risk. The dosimetric advantages of the noncoplanar and oblique arcs require careful beam angle selection during treatment planning to avoid collisions during treatment, which may be facilitated by commercial software.

Cardiac motion and its dosimetric impact during radioablation for refractory ventricular tachycardia.

INTRODUCTION: Cardiac radioablation (CR) is a noninvasive treatment option for patients with refractory ventricular tachycardia (VT) during which high doses of radiation, typically 25 Gy, are delivered to myocardial scar. In this study, we investigate motion from cardiac cycle and evaluate the dosimetric impact in a cohort of patients treated with CR. METHODS: This retrospective study included eight patients treated at our institution who had respiratory-correlated and ECG-gated 4DCT scans acquired within 2 weeks of CR. Deformable image registration was applied between maximum systole (SYS) and diastole (DIAS) CTs to assess cardiac motion. The average respiratory-correlated CT (AVGresp ) was deformably registered to the average cardiac (AVGcardiac ), SYS, and DIAS CTs, and contours were propagated using the deformation vector fields (DVFs). Finally, the original treatment plan was recalculated on the deformed AVGresp CT for dosimetric assessment. RESULTS: Motion magnitudes were measured as the mean (SD) value over the DVFs within each structure. Displacement during the cardiac cycle for all chambers was 1.4 (0.9) mm medially/laterally (ML), 1.6 (1.0) mm anteriorly/posteriorly (AP), and 3.0 (2.8) mm superiorly/inferiorly (SI). Displacement for the 12 distinct clinical target volumes (CTVs) was 1.7 (1.5) mm ML, 2.4 (1.1) mm AP, and 2.1 (1.5) SI. Displacements between the AVGresp and AVGcardiac scans were 4.2 (2.0) mm SI and 5.8 (1.4) mm total. Dose recalculations showed that cardiac motion may impact dosimetry, with dose to 95% of the CTV dropping from 27.0 (1.3) Gy on the AVGresp to 20.5 (7.1) Gy as estimated on the AVGcardiac . CONCLUSIONS: Cardiac CTV motion in this patient cohort is on average below 3 mm, location-dependent, and when not accounted for in treatment planning may impact target coverage. Further study is needed to assess the impact of cardiac motion on clinical outcomes.

A multi-institutional pilot clinical trial of spectroscopic MRI-guided radiation dose escalation for newly diagnosed glioblastoma.

Background: Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Methods: Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Conclusion: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

Randomized Trial of Conventional Versus Conventional Plus Fluciclovine (18F) Positron Emission Tomography/Computed Tomography-Guided Postprostatectomy Radiation Therapy for Prostate Cancer: Volumetric and Patient-Reported Analyses of Toxic Effects.

PURPOSE: Postprostatectomy radiation therapy planning with fluciclovine (18F) positron emission tomography (PET)/computed tomography has demonstrated improved disease-free survival over conventional only (computed tomography- or magnetic resonance imaging-based) treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTVs) without increasing patient-reported toxic effects. METHODS AND MATERIALS: From 2012 to 2019, 165 postprostatectomy patients with detectable prostate-specific antigen were randomized (arm 1 [no PET]: 82; arm 2 [PET]: 83). Prostate bed target volumes with (CTV1: 45.0-50.4 Gy/1.8 Gy) or without (CTV2/CTV: 64.8-70.2 Gy/1.8 Gy) pelvic nodes, as well as organ-at-risk doses, were compared pre- versus post-PET (arm 2) using the paired t test and between arms using the t test. Patient-reported outcomes used International Prostate Symptom Score and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Univariate and multivariable analyses were performed and linear mixed models were fitted. RESULTS: Median follow-up of the whole cohort was 3.52 years. All patients had baseline patient-reported outcomes, 1 patient in arm 1 and 3 patients in arm 2 withdrew, and 4 arm 2 patients had extrapelvic uptake on PET with radiotherapy aborted, leaving 81 (arm 1) and 76 patients (arm 2) for analysis of toxic effects. Mean CTV1 (427.6 vs 452.2 mL; P = .462, arm 1 vs arm 2) and CTV2/CTV (137.18 vs 134.2 mL; P = .669) were similar before PET incorporation. CTV1 (454.57 vs 461.33 mL; P = .003) and CTV2/CTV (134.14 vs 135.61 mL; P < .001) were modestly larger after PET incorporation. Although V40 Gy (P = .402 and P = .522 for rectum and bladder, respectively) and V65 Gy (P = .157 and P = .182 for rectum and bladder, respectively) were not significantly different pre- versus post-PET, penile bulb dose significantly increased post-PET (P < .001 for both V40 Gy and V65 Gy). On univariate and multivariable analyses, arm was not significant for any EPIC-CP subdomain. International Prostate Symptom Score and EPIC-CP linear mixed models were not significantly different between arms. CONCLUSIONS: Despite larger CTVs after incorporation of fluciclovine (18F) PET, we found no significant difference in patient-reported toxic effects with long-term follow-up.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.

Onboard cone-beam CT-based replan evaluation for head and neck proton therapy.

PURPOSE: Quality assurance computed tomography (QACT) is the current clinical practice in proton therapy to evaluate the needs for replan. QACT could falsely indicate replan because of setup issues that would be solved on the treatment machine. Deforming the treatment planning CT (TPCT) to the pretreatment CBCT may eliminate this issue. We investigated the performance of replan evaluation based on deformed TPCT (TPCTdir) for proton head and neck (H&N) therapy. METHODS AND MATERIALS: Twenty-eight H&N datasets along with pretreatment CBCT and QACT were used to validate the method. The changes in body volume were analyzed between the no-replan and replan groups. The dose on the TPCTdir, the deformed QACT (QACTdir), and the QACT were calculated by applying the clinical plans to these image sets. Dosimetric parameters' changes, including ΔD95, ΔDmean, and ΔD1 for the clinical target volumes (CTVs) were calculated. Receiver operating characteristic curves for replan evaluation based on ΔD95 on QACT and TPCTdir were calculated, using ΔD95 on QACTdir as the reference. A threshold for replan based on ΔD95 on TPCTdir is proposed. The specificities for the proposed method were calculated. RESULTS: The changes in the body contour were 95.8 ± 83.8 cc versus 305.0 ± 235.0 cc (p < 0.01) for the no-replan and replan groups, respectively. The ΔD95, ΔDmean, and ΔD1 are all comparable for all the evaluations. The differences between TPCTdir and QACTdir evaluations were 0.30% ± 0.86%, 0.00 ± 0.22 Gy, and -0.17 ± 0.61 Gy for CTV ΔD95, ΔDmean, and ΔD1, respectively. The corresponding differences between the QACT and QACTdir were 0.12% ± 1.1%, 0.02 ± 0.32 Gy, and -0.01 ± 0.71 Gy. CTV ΔD95 > 2.6% in TPCTdir was chosen as the threshold to trigger QACT/replan. The corresponding specificity was 94% and 98% for the clinical practice and the proposed method, respectively. CONCLUSIONS: The replan evaluation based on TPCTdir provides better specificity than that based on the QACT.

The Contribution of Thoracic Radiation Dose Volumes to Subsequent Development of Cardiovascular Disease in Cancer Survivors.

BACKGROUND: Although radiation therapy (RT) has been recognized for contributing to cardiovascular disease (CVD), it is unknown whether specific doses received by cardiovascular tissues influence development. OBJECTIVE: In this pilot study, we examined the contribution of RT dose distribution on the development of CVD events in patients with cancer within 5 years of RT. METHODS: A retrospective case-controlled design was used matching 28 cases receiving thoracic RT who subsequently developed an adverse CVD event with 28 controls based upon age, gender, and cancer type. Dose volume histograms of nongated computed tomography scans received during RT characterized the dose delivered to the heart. Heart chambers were segmented using an atlas approach, and radiomics features for the segmentation as well as planning dose in each chamber were tabulated for analysis. RESULT: No significant differences were observed in the RT dose statistics between groups, preexisting CVD, nor significant differences of RT doses delivered to distinct chambers of the heart. Cases were found to have greater CVD risk factors at the time of cancer diagnosis. Morphological significant differences for perimeter on border ( P = .043), equivalent spherical radius ( P = .050), and elongation ( P = .038) were observed, with preexisting CVD having the highest values (ie, larger hearts). CONCLUSION: Traditional CVD risk factors were more prevalent in the cases who developed CVD. No differences were observed in doses of RT. Of note, we observed significant differences in heart morphology and mass in known diseased hearts on the pretreatment scans. These new metrics may have implications for the measurement and quantification of CVD.

3D whole-brain metabolite imaging to improve characterization of low-to-intermediate grade gliomas.

PURPOSE: MRI is the standard imaging modality used for diagnosis, treatment planning, and post-treatment management of gliomas. Contrast-enhanced T1-weighted (CE-T1w) MRI is used to plan biopsy and radiation for grade IV gliomas but is less effective for grade II and III gliomas (i.e., low-to-intermediate grade gliomas) which may have minimal or no enhancement. Magnetic resonance spectroscopic imaging (MRSI) is an advanced MRI technique that has been shown, to improve diagnostic yield of biopsy and target delineation for grade IV glioma. The purpose of this study is to determine if MRSI can improve characterization and tissue sampling of low-to-intermediate grade gliomas. METHODS: Prospective grade II and grade III glioma patients were enrolled to undergo whole brain high-resolution MRSI prior to tissue sampling. Choline/N-acetyl-aspartate (Cho/NAA) maps were overlaid on anatomic imaging and imported into stereotactic biopsy software. Patients were treated with standard-of-care surgery and radiation. Volumes of spectroscopically abnormal tissue were generated and compared with anatomic imaging and areas of enhancing recurrence on follow-up imaging. RESULTS: Ten patients had pathologic diagnosis of grade II (n = 4) or grade III (n = 6) with a median follow-up of 27.3 months. Five patients had recurrence, and regions of recurrence were found to overlap with metabolically abnormal regions on MRSI at the time of diagnosis. CONCLUSION: MRSI in low-to-intermediate grade glioma patients is predictive of areas of subsequent recurrence. Larger studies are needed to determine if MRSI can be used to guide surgical and radiation treatment planning in these patients.

18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.

BACKGROUND: Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy. METHODS: In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants. FINDINGS: From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06-3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group). INTERPRETATION: Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study. FUNDING: National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.

Dosimetric Factors Related to Radiation Necrosis After 5-Fraction Radiosurgery for Patients With Resected Brain Metastases.

PURPOSE: Stereotactic radiosurgery (SRS) is increasingly used in the management of patients with resected brain metastases (rBMs). A significant complication of this therapy can be radiation necrosis (RN). Despite radiation therapy dose de-escalation and the delivery of several rather than a single dose fraction, rates of RN after SRS for rBMs remain high. We evaluated the dosimetric parameters associated with radiographic RN for rBMs. METHODS AND MATERIALS: From 2008 to 2016, 55 rBMs at a single institution that were treated postoperatively with 5-fraction linear accelerator-based SRS (25-35 Gy) with minimum 3 months follow-up were evaluated. For each lesion, variables recorded included radiation therapy dose to normal brain, location and magnitude of hotspots, clinical target volume (CTV), and margin size. Hotspot location was stratified as within the tumor bed alone (CTV) or within the planning target volume (PTV) expansion margin volume (PTV minus CTV). Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence. Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. RESULTS: Median age for all patients was 58.5 years. For all targets, the median CTV was 17.53 cm3, the median expansion margin to PTV was 2 mm, and the median max hotspot was 111%. At 1 year, cumulative incidence of radiographic RN was 18.2%. Univariate analysis showed that max hotspots with a hazard ratio of 3.28 (P = .045), hotspots within the PTV expansion margin with relative magnitudes of 105%, 110%, and 111%, and an absolute dose of 33.5 Gy predicted for RN (P = .029, P = .04, P = .038, and P = .0488, respectively), but hotspots within the CTV did not. CONCLUSIONS: To our knowledge, this is the first study that investigated dosimetric factors that predict for RN after 5-fraction hypofractionated SRS for rBM. Hotspot location and magnitude appear important for predicting RN risk, thus these parameters should be carefully considered during treatment planning.

Prospective International Pilot Study Evaluating the Efficacy of a Self-Guided Contouring Teaching Module With Integrated Feedback for Transitioning From 2D to 3D Treatment Planning.

PURPOSE: Transitioning from two-dimensional to three-dimensional treatment planning requires developing contouring skills. Contouring atlases are excellent resources, but they do not provide users active feedback. Developing countries may not have many radiation oncologists experienced in three-dimensional planning to provide training. We sought to develop a standardized self-guided educational module with integrated feedback to teach contouring skills. METHODS AND MATERIALS: All 18 oncology residents at Black Lion Hospital/Addis Ababa University in Ethiopia were trained to contour the level II lymph node station. Residents took a baseline pretest quiz, survey, and contouring evaluation. Residents then watched an instructional contouring lecture and performed three additional cases with integrated feedback by comparing their contours to gold-standard contours. Residents then took a post-training quiz, survey, and contouring evaluation. Paired t tests and analysis of variance were used for analysis. RESULTS: Before training, the average number of total cases ever contoured was 2.4 and the average number of head and neck cases contoured was 0.5. Comfort with contouring improved from being "not at all comfortable" to "quite comfortable" after the 3-hour training (P < .001). The standard deviation between the resident contours and gold standard improved from 72.6 cm3 (pretest) to 7.4 cm3 (post-test). The average percentage overlap with the gold-standard contours and Dice similarity coefficient improved with each case performed, from 27.7% and 0.26 (pretest) to 80.1% and 0.77 (post-test), respectively (P < .001). After training, 16 of 18 (88.9%) residents produced a Dice similarity coefficient greater than 0.7, the threshold generally accepted for excellent agreement. CONCLUSION: This self-guided teaching module was an effective tool for developing level II lymph node contouring skills by providing active feedback and resulted in improved user confidence and accuracy compared with a gold standard. This module can be expanded to other disease sites and countries to further facilitate transitioning to three-dimensional treatment planning in developing countries.

Assessing Treatment Response of Glioblastoma to an HDAC Inhibitor Using Whole-Brain Spectroscopic MRI.

Histone deacetylases regulate a wide variety of cellular functions and have been implicated in redifferentiation of various tumors. Histone deacetylase inhibitors (HDACi) are potential pharmacologic agents to improve outcomes for patients with gliomas. We assessed the therapeutic efficacy of belinostat (PXD-101), an HDACi with blood-brain barrier permeability. Belinostat was first tested in an orthotopic rat glioma model to assess in vivo tumoricidal effect. Our results showed that belinostat was effective in reducing tumor volume in the orthotopic rat glioma model in a dose-dependent manner. We also tested the antidepression activity of belinostat in 2 animal models of depression and found it to be effective. Furthermore, we confirmed that myo-inositol levels improved by belinostat treatment in vitro. In a human pilot study, it was observed that belinostat in combination with chemoradiation may delay initial recurrence of disease. Excitingly, belinostat significantly improved depressive symptoms in patients with glioblastoma compared with control subjects. Finally, spectroscopic magnetic resonance imaging of 2 patient cases from this pilot study are presented to indicate how spectroscopic magnetic resonance imaging can be used to monitor metabolite response and assess treatment effect on whole brain. This study highlights the potential of belinostat to be a synergistic therapeutic agent in the treatment of gliomas.

The Brain Imaging Collaboration Suite (BrICS): A Cloud Platform for Integrating Whole-Brain Spectroscopic MRI into the Radiation Therapy Planning Workflow.

Glioblastoma has poor prognosis with inevitable local recurrence despite aggressive treatment with surgery and chemoradiation. Radiation therapy (RT) is typically guided by contrast-enhanced T1-weighted magnetic resonance imaging (MRI) for defining the high-dose target and T2-weighted fluid-attenuation inversion recovery MRI for defining the moderate-dose target. There is an urgent need for improved imaging methods to better delineate tumors for focal RT. Spectroscopic MRI (sMRI) is a quantitative imaging technique that enables whole-brain analysis of endogenous metabolite levels, such as the ratio of choline-to-N-acetylaspartate. Previous work has shown that choline-to-N-acetylaspartate ratio accurately identifies tissue with high tumor burden beyond what is seen on standard imaging and can predict regions of metabolic abnormality that are at high risk for recurrence. To facilitate efficient clinical implementation of sMRI for RT planning, we developed the Brain Imaging Collaboration Suite (BrICS; https://brainimaging.emory.edu/brics-demo), a cloud platform that integrates sMRI with standard imaging and enables team members from multiple departments and institutions to work together in delineating RT targets. BrICS is being used in a multisite pilot study to assess feasibility and safety of dose-escalated RT based on metabolic abnormalities in patients with glioblastoma (Clinicaltrials.gov NCT03137888). The workflow of analyzing sMRI volumes and preparing RT plans is described. The pipeline achieved rapid turnaround time by enabling team members to perform their delegated tasks independently in BrICS when their clinical schedules allowed. To date, 18 patients have been treated using targets created in BrICS and no severe toxicities have been observed.