AbstractPurpose: Pharmacologic ascorbate (P-AscH−) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH− with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH− in humans. Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7–26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. Conclusions: P-AscH− combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255

T2* relaxation in GBM and normal tissue.

BACKGROUND Mesenchymal chondrosarcoma (MCS) is an aggressive subtype of chondrosarcoma that occurs extremely rarely in the central nervous system. Patients often present with pain or sensorimotor deficits, and resection is considered the gold standard. The role of adjuvant radiation and/or chemotherapy is largely unknown. OBSERVATIONS A 22-year-old male presented with a 4-month history of progressive back and bilateral leg pain. He underwent imaging workup with magnetic resonance imaging of the lumbar spine and was found to have an intradural, extramedullary, heterogeneously enhancing mass spanning the L4–5 vertebral levels. Intraoperatively, a lobular, partially calcified mass with a ventral dural attachment displacing the nerve roots laterally was observed. The mass was removed en bloc, and the patient later underwent adjuvant radiotherapy, with no evidence of recurrence 2 years following surgery. LESSONS Spinal MCS is extremely rare and often presents with a more aggressive course than conventional chondrosarcoma. Radiological diagnosis is challenging, as the tumor mimics different pathologies. The presence of calcifications, heterogeneous enhancement, and a more rapid clinical course as well as the presence of HEY1::NCOA2 gene fusion, which can be detected by surrogate immunohistochemistry, aids in diagnosis. Resection is the standard of care, and adjuvant radiation may be considered to reduce local recurrence, although further studies are warranted.

Purpose:The purpose of this work was to investigate the use of a segmentation approach that could potentially improve the speed and reproducibility of contouring during magnetic resonance-guided adaptive radiation therapy. Methods and Materials:The segmentation algorithm was based on a hybrid deep neural network and graph optimization approach that also allows rapid user intervention (Deep layered optimal graph image segmentation of multiple objects and surfaces [LOGISMOS] + just enough interaction [JEI]). A total of 115 magnetic resonance-data sets were used for training and quantitative assessment. Expert segmentations were used as the independent standard for the prostate, seminal vesicles, bladder, rectum, and femoral heads for all 115 data sets. In addition, 3 independent radiation oncologists contoured the prostate, seminal vesicles, and rectum for a subset of patients such that the interobserver variability could be quantified. Consensus contours were then generated from these independent contours using a simultaneous truth and performance level estimation approach, and the deviation of Deep LOGISMOS + JEI contours to the consensus contours was evaluated and compared with the interobserver variability. Results:The absolute accuracy of Deep LOGISMOS + JEI generated contours was evaluated using median absolute surface-to-surface distance which ranged from a minimum of 0.20 mm for the bladder to a maximum of 0.93 mm for the prostate compared with the independent standard across all data sets. The median relative surface-to-surface distance was less than 0.17 mm for all organs, indicating that the Deep LOGISMOS + JEI algorithm did not exhibit a systematic under- or oversegmentation. Interobserver variability testing yielded a mean absolute surface-to-surface distance of 0.93, 1.04, and 0.81 mm for the prostate, seminal vesicles, and rectum, respectively. In comparison, the deviation of Deep LOGISMOS + JEI from consensus simultaneous truth and performance level estimation contours was 0.57, 0.64, and 0.55 mm for the same organs. On average, the Deep LOGISMOS algorithm took less than 26 seconds for contour segmentation. Conclusions:Deep LOGISMOS + JEI segmentation efficiently generated clinically acceptable prostate and normal tissue contours, potentially limiting the need for time intensive manual contouring with each fraction.

Supplemental Figure 1: P-AscH- treatment in combination with RT and TMZ decreases the systemic the systemic oxidaitive stress marker 4-hydroxy-2-nonenal modified proteins. S1A-SAB.

Background: Recurrent in-frame insertions within exon 20 causing duplication of amino acids TyrosineValine-Methionine-Alanine (YVMA) represent 80% of all HER2 alterations in non-small cell lung cancer (NSCLC). HER2 tyrosine kinase inhibitors (TKI), anti-HER2 monoclonal antibodies and HER2 directed antibody-drug conjugates have been evaluated in patients with HER2 mutated NSCLC. Limited data are available regarding the activity of these agents in exon 19 alterations. Osimertinib, a 3rd generation EGFRTKI, has been found in pre-clinical studies to decrease growth of NSCLC with HER2 exon 19 aberrations. Case Description: A 68-year-old female with a past medical history of type 2 diabetes and minimal smoking was diagnosed with stage IV NSCLC. Next generation sequencing on tumor tissue demonstrated an ERBB2 exon 19 c.2262_2264delinsTCC, p.(L755P) mutation. After five lines of treatment that included chemotherapy, chemoimmunotherapy and investigational agents the patient's disease was progressing. At this time her functional status remained good, therefore clinical trials were explored however, none were available. Based on findings from pre-clinical studies, the patient was commenced on osimertinib 80 mg OD and achieved a partial response (PR) according to RESIST criteria both intra- and extracranially. Conclusions: This is the first report to our knowledge to demonstrate activity of osimertinib in a patient with NSCLC harboring HER2 exon 19, p. L755P mutation resulting in intra- and extracranial response. In the future, osimertinib could become a targeted treatment for patients harboring Exon19 ERBB2 point mutations.

MR-guided adaptive radiotherapy (MRgART) provides opportunities to benefit patients through enhanced use of advanced imaging during treatment for many patients with various cancer treatment sites. This novel technology presents many new challenges which vary based on anatomic treatment location, technique, and potential changes of both tumor and normal tissue during treatment. When introducing new treatment sites, considerations regarding appropriate patient selection, treatment planning, immobilization, and plan-adaption criteria must be thoroughly explored to ensure adequate treatments are performed. This paper presents an institution's experience in developing a MRgART program for a 1.5T MR-linac for the first 234 patients. The paper suggests practical treatment workflows and considerations for treating with MRgART at different anatomical sites, including imaging guidelines, patient immobilization, adaptive workflows, and utilization of bolus.

Pharmacological ascorbate (P-AscH ) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe3+) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe2+). Because paramagnetic Fe3+ may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH-induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe3+ or Fe2+ were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH infusion, post-P-AscH infusion, and post-radiation (3-4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe3+ and Fe2+ gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe3+ demonstrated detectable changes in T2* and QSM relaxation times relative to Fe2+ phantoms. Compared to pre-P-AscH , GBM T2* and QSM imaging were significantly changed post-P-AscH infusion consistent with conversion of Fe3+ to Fe2+. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH inducing greater changes in tumor labile iron pools compared to the normal tissue. Conclusions: T2* and QSM MR-imaging responses are consistent with P-AscH reducing Fe3+ to Fe2+, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH -induced changes in redox-active iron.

Abstract Pharmacological ascorbate (P-AscH-; high dose intravenous infusions of vitamin C generating milli-molar plasma concentrations) has re-emerged as an anti-cancer therapy. Phase 1 clinical trials combining P-AscH- with chemotherapy and ionizing radiation demonstrate safety and promising clinical outcomes in a variety of malignancies. In a first-in-human trial, subjects with newly diagnosed glioblastoma (GBM) and undetectable MGMT promoter methylation were treated with P-AscH-, ionizing radiation, and temozolomide. Results demonstrate median progression-free survival (PFS) of 10 months and median overall survival (OS) of 23 months, comparing favorably to historical GBM patients expressing MGMT. P-AscH-‘s anti-cancer mechanism is dependent upon the presence of redox active labile iron. In the presence of redox active iron, the formation of hydrogen peroxide, which causes oxidative stress and eventual cell death, selectively forms in cancer cells. Treatment with P-AscH- increased cancer cells’ labile iron pool, further enhancing sensitivity to P-AscH-. We investigated the capability of MR imaging (T2* relaxation time) to measure the redox active iron and predict response to P-AscH-. T2* relaxation time is influenced by in-field inhomogeneities, such as redox active paramagnetic iron. The active phase 2 trial evaluating P-AscH-, radiation, and temozolomide for GBM, obtains T2* imaging prior to (baseline) and immediately after ascorbate infusion (NCT02344355). A preliminary analysis of the baseline scan for the first 15 subjects suggests those with faster GBM T2* relaxation times (≤ 58 ms) have more redox active labile iron pools as well as an improved median PFS (11.4 months) compared to those with slower T2* relaxation times (> 58 ms; median PFS of 8.5 months). Pre-clinical studies evaluating the effectiveness of iron nano-particle supplementation in GBM animal models are on-going. (Supported by P01 CA217797, R01 CA169046, U01 CA140206, T32 CA078586, P30 CA086862, as well as the Gateway for Cancer Research grant G-17–1500.)

Purpose: The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP. Methods and Materials: Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected. Patients were excluded for pathologic seminal vesicle or lymph node involvement, metastatic disease, pre-RP PSA ≥ 30, or adjuvant (nonsalvage) radiation therapy or hormone therapy. The primary endpoint was biochemical relapse free survival (bRFS), where PSA failure was defined as PSA > 0.10 ng/mL and rising, or at salvage intervention. The Kaplan-Meier method was employed for bRFS estimates; recursive partitioning analysis using cumulative or single maximal margin extent (ME) and Gleason grade (GG) at RP was applied to identify variables associated with bRFS. Results: At median follow-up of 105 months, 210 patients with positive margins at RP were eligible for analysis, and 89 had experienced PSA relapse. Median age was 61 years (range, 43-76), and median pre-RP PSA 5.8 ng/mL (1.6-26.0). Recursive partitioning analysis yielded 5 discrete risk groups, with the lowest risk group (GG1, ≤ 2 mm ME) demonstrating a bRFS of 92% at 8 years compared with the highest risk group (GG3-5, ≥ 3 mm ME) of 11%. Conclusions: This retrospective study suggests that it may be possible to risk-stratify patients undergoing margin-positive RP using commonly acquired clinical and pathologic variables. Patients with low-grade tumors and minimally involved margins have a very low recurrence risk and may be able to forego postprostatectomy radiation. Meanwhile, those with higher grade and greater involvement could benefit from adjuvant or early salvage radiation therapy.

BACKGROUND: Renal cell carcinoma with metastases to the spine (RCCMS) requires a multidisciplinary approach. We reviewed our institutional experience with RCCMS patients undergoing spinal surgery in order to identify factors that may affect clinical outcomes, survival, and complications. METHODS: Patients with RCCMS who underwent operative intervention from 2007 to 2020 were reviewed retrospectively. RESULTS: Forty-four patients with the diagnosis of RCCMS were identified. Pain was the most common symptom, and neurologic dysfunction was present in one third of cases. Thoracic spine was the most common location (N = 27), followed by the lumbar (N = 12) and cervical (N = 5) regions. The overall survival from diagnosis of renal cell carcinoma was 25 (2 - 194) months and 8 (0.3 - 92) months after spinal surgery. Gender, age, spinal level, postoperative radiation, and nephrectomy had no bearing on survival. Survival for patients with a Tokuhashi score of 0 - 8, 9 - 11, and 12 - 15 was 6.5 (1.5 - 23.5), 8.9 (0.3 - 91.6), and 23.4 (2.5 - 66) months, respectively (P = 0.03). The postoperative American Spinal Cord Injury Association score of E (hazard ratio 0.109 [95% confidence interval 0.022 - 0.534, P = 0.006) also bore a significant influence on survival. There was a total of 10 complications in 7 of 44 (16%) patients. CONCLUSIONS: Median postoperative survival of patients with RCCMS was 8 (0.3 - 92) months. Higher Tokuhashi score and ASIA E score at follow-up correlated with improved overall survival. Complication rate was 16%. Spinal surgery in RCCMS is indicated for the preservation of function and prevention of neurologic deterioration. Multimodality therapy with improved chemotherapy and stereotactic spinal radiation is expected to impact quality and length of survival positively.

Objective: The histopathology of intramedullary spinal cord tumors (IMSCT) can be suspected from the MRI features and characteristics. Ultimately, the confirmation of diagnosis requires surgery. This retrospective study addresses MRI features including homogeneity of enhancement, margination, and associated syrinx in intramedullary astrocytomas (IMA) and ependymomas (IME) that assist in diagnosis and predict resectability of these tumors. Methods: Single-center retrospective analysis of IMA and IME cases since 2005 extracted from the departmental registry/electronic medical records post IRB approval (IRB 201,710,760). We compared imaging findings (enhancement, margination, homogeneity, and associated syrinxes) between tumor types and examined patient outcomes. Results: There were 18 IME and 21 IMA. On preoperative MRI, IME was favored to have homogenous enhancement (OR 1.8, p = 0.0001), well-marginated (p < 0.0001, OR 0.019 [95 % CI 0.0020.184]), and associated syrinx (p = 0.015, OR 0.192 [95 % CI 0.049-0.760]). Total excision, subtotal excision, and biopsy were performed in 12, 5, and 1 patients in the IME cohort, respectively. In the IMA group, tumors were heterogeneous and poorly marginated in 20 of the 21 patients. Total excision, subtotal excision, and biopsy were undertaken in 2, 13, and 6 patients, respectively. The success of excision was predicted by MRI, with a significant difference in the extent of resection between IME and IMA (X-2 =14.123, p = 0.001). In terms of outcome, ordinal regression analysis showed that well-margined tumors and those with homogeneous enhancement were associated with a better postoperative McCormick score. Extent of resection had statistically significant survival (p = 0.026) and recurrence-free survival (p = 0.008) benefits. Conclusion: The imaging characteristics of IME and IMA have meaningful clinical significance. Homogeneity, margination, and associated syrinxes in IME can predict resectability and complexity of surgery.

Abstract Purpose To determine if the gamma knife icon (GKI) can provide superior stereotactic radiotherapy (SRT) dose distributions for appropriately selected meningioma and post‐resection brain tumor bed treatments to volumetric modulated arc therapy (VMAT). Materials and Methods Appropriately selected targets were not proximal to great vessels, did not have sensitive soft tissue including organs‐at‐risk (OARs) within the planning target volume (PTV), and did not have concave tumors containing excessive normal brain tissue. Four of fourteen candidate meningioma patients and six of six candidate patients with brain tumor cavities were considered for this treatment planning comparison study. PTVs were generated for GKI and VMAT by adding 1 mm and 3 mm margins, respectively, to the GTVs. Identical PTV V100%‐values were obtained for the GKI and VMAT plans for each patient. Meningioma and tumor bed prescription doses were 52.7–54.0 in 1.7–1.8 Gy fractions and 25 Gy in 5 Gy fractions, respectively. GKI dose rate was 3.735 Gy/min for 16 mm collimators. Results PTV radical dose homogeneity index was 3.03 ± 0.35 for GKI and 1.27 ± 0.19 for VMAT. Normal brain D 1%, D 5%, and D 10% were lower for GKI than VMAT by 45.8 ± 10.9%, 38.9 ± 11.5%, and 35.4 ± 16.5% respectively. All OARs considered received lower maximum doses for GKI than VMAT. GKI and VMAT treatment times for meningioma plans were 12.1 ± 4.13 min and 6.2 ± 0.32 min, respectively, and, for tumor cavities, were 18.1 ± 5.1 min and 11.0 ± 0.56 min, respectively. Conclusions Appropriately selected meningioma and brain tumor bed patients may benefit from GKI‐based SRT due to the decreased normal brain and OAR doses relative to VMAT enabled by smaller margins. Care must be taken in meningioma patient selection for SRT with the GKI, even if they are clinically appropriate for VMAT.

Standard manual contouring of meningiomas is time consuming and introduces substantial inconsistencies. A user-friendly segmentation tool could reduce physician workload and improve reproducibility. Sixteen cases of treated meningiomas were used for development of a 3-dimensional LOGISMOS (Layered Optimal Graph Image Segmentation for Multiple Objects and Surfaces) based solution for segmentation. The automated LOGISMOS method is started by placing a sphere encompassing the tumor. Starting from the center of the sphere, columns of graph nodes are constructed. LOGISMOS segmentation finds the optimal set of graph nodes on the boundary with minimum total cost. Prior knowledge such as the shape and anatomy of the target constrains segmentation. If needed, errors in automated segmentation are corrected by the user interaction with the algorithm rather than manually slice-by-slice. This process uses our just enough interaction (JEI) approach that considers the expert hints pointing to the correct boundary locations to modify segmentation cost functions and search for a new optimal solution. The 16 cases were manually contoured, then contoured using the JEI-LOGISMOS segmentation tool by two central nervous system experts. Cases were randomly displayed for both manual and JEI-LOGISMOS analyses in several sessions to avoid bias. Segmentation accuracy indices were determined as continuous variables: mean (± standard deviations) or median (and interquartile ranges IQR) where appropriate. Computer-analysis accuracy was evaluated using point-wise 3D surfaces distance errors and volumetric linear regression. To assess reproducibility, Dice coefficient along with 3D relative volume difference (RVD) were obtained. To evaluate the efficiency of the automated method, time required for automated contouring with JEI and manual contouring was compared using Wilcoxon signed-rank test. Our 3D LOGISMOS segmentations with JEI of both experts achieved sub-voxel precision (voxel size ∼1 mm) for meningioma tumor surfaces (JEI signed error: 0.86 ± 1.82 mm for expert 1, 0.24 ± 1.26 mm for expert 2) and provided accurate volume measurements in comparison to manual contouring (volume regression: R2 = 0.93, p < 0.001 for expert 1, R2 = 0.96, p<0.001 for expert 2;). The inter-observer variability of automated contouring showed better reproducibility compared to manual contouring (Dice: 87.4% vs. 83.6%; RVD: -1.1% vs. 14.9%). Median time required for contouring one case was significantly reduced for both experts (-204 seconds, p = 0.01, 46.5% faster for expert 1 and -228 seconds, p = 0.04, 35.8% faster for expert 2.). Automated contouring using a JEI approach following the automated 3D LOGISMOS segmentation improves reproducibility and efficiency of contouring for meningiomas. Volumes obtained using manual tracing and JEI-LOGISMOS were highly comparable.

Background This meta-analysis describes the validity of narrow band imaging (NBI) in the assessment of suspicious oral lesions. Methods Medline, EMBASE, and Scopus were searched for trial studies comparing NBI with conventional modalities in the oral cavity (OC) and oropharynx (OP) for the detection of dysplastic and malignant change. Results Seven studies were found, and generally supported the utility of NBI in different clinical settings, although there were exceptions. Pooled data from 4 studies of NBI validity demonstrated high summary specificity and sensitivity for a wide range of suspicious lesions of the OC or OP (75.7% with 95% CI 65.1%-83.9%, and 91.5% with 95% CI 81.8%-96.3%, respectively). Summary positive likelihood ratio (LR+) was 8.91 (95% CI 4.1-19.6) and 0.27 (95% CI 0.18-0.39), respectively. Conclusions NBI is a promising diagnostic and surveillance tool for suspicious lesions in the OC or OP; however, higher powered studies will define precise NBI criterion and clinical recommendations.

AbstractPurpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH−) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH− to standard RT/TMZ therapy. Patients and Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH−) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH− phase). Eight P-AscH− dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH− doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH− was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). Results: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. Conclusions: P-AscH−/RT/TMZ is safe with promising clinical outcomes warranting further investigation.

Purpose: The number of studies that evaluate treatment margins for high grade gliomas (HGG) are limited. We hypothesize that patients with HGG who are treated with a gross tumor volume (GTV) to planning tumor volume (PTV) expansion of <= 1 cm will have progression-free survival (PFS) and overall survival (OS) rates similar to those treated in accordance with standard protocols by the Radiation Therapy Oncology Group or European Organisation for Research and Treatment of Cancer. Furthermore, the PFS and OS of subgroups within the study population will have equivalent survival outcomes with GTVI-to-PTVI margins of 1.0 cm and 0.4 cm. Methods and materials: Treatment plans and outcomes for patients with pathologically confirmed HGG were analyzed (n= 267). Survival (PFS and OS) was calculated from the time of the first radiation treatment and a chi(2) test or Fisher exact test was used to calculate the associations between margin size and patient characteristics. Survival was estimated using Kaplan-Meier and compared using the log-rank test. All analyses were performed on the univariate level. ResultsThe median PFS and OS times were 10.6 and 19.1 months, respectively. By disease, the median PFS and OS times were 8.6 and 16.1 months for glioblastoma and 26.7 and 52.5 months for anaplastic glioma. The median follow-up time was 18.3 months. The treatment margin had no effect on outcome and the 1.0 cm GTV1-PTV1 margin subgroup (n = 212) showed median PFS and OS times of 10.7 and 19.1 months, respectively, and the 0.4 cm margin subgroup (n = 55) 10.2 and 19.3 months, respectively. In comparison with the standard treatment with 2 cm to 3 cm margins, there was not a significant difference in outcomes. Conclusions: Them is no apparent difference in survival when utilizing smaller versus larger margins as defined by the guidelines of the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer. Although there remains no class I evidence that outcomes after treatment with smaller margins are identical to those after treatment with larger margins, this large series with long-term follow up suggests that a reduction of the margins is safe and further investigation is wananted. (C) 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.