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Importance Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, setting, and participants The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions Chemoradiation and consolidation chemotherapy with or without metformin. Main outcomes and measures The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and relevance In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial registration ClinicalTrials.gov Identifier: NCT02186847.

Background and purpose To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). Methods 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively. Results Median follow-up was 34.8months. Two year Kaplan–Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009–197, HR=1.005, p -value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003–70, HR=1.025, p -value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death. Conclusions Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied.

// Matthias Holdhoff 1 , Gregory J. Cairncross 2 , Thomas M. Kollmeyer 3 , Ming Zhang 1 , Peixin Zhang 4 , Minesh P. Mehta 5 , Maria Werner-Wasik 6 , Luis Souhami 7 , Jean-Paul Bahary 8 , Young Kwok 5 , Alan C. Hartford 9 , Arnab Chakravarti 10 , Srinivasan Yegnasubramanian 1 , Bert Vogelstein 1 , Nickolas Papadopoulos 1 , Kenneth Kinzler 1 , Robert B. Jenkins 3 and Chetan Bettegowda 1 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 2 Charbonneau Cancer Institute at the University of Calgary, Calgary, AB, USA 3 Mayo Clinic, Rochester, MN, USA 4 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA 5 University of Maryland Medical Center, Baltimore, MD, USA 6 Thomas Jefferson University Hospital, Philadelphia, PA, USA 7 McGill University Health Centre, Montreal, QC, Canada 8 Centre Hospitalier de l’Universite de Montreal, Montreal University, Montreal, QC, Canada 9 Darthmouth-Hitchcock Medical Center, Lebanon, NH, USA 10 The Ohio State University, Columbus, OH, USA Correspondence to: Matthias Holdhoff, email: // Chetan Bettegowda, email: // Keywords : oligodendroglioma, chemotherapy, survival, genomics, co-deletion 1p/19q Received : October 01, 2016 Accepted : March 21, 2017 Published : March 31, 2017 Abstract Background: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of

Purpose: The study was aimed to compare online 6 degree-of-freedom image registrations of TrueBeam cone-beam computed tomography and BrainLab ExacTrac X-ray imaging systems for intracranial radiosurgery. Methods: Phantom and patient studies were performed on a Varian TrueBeam STx linear accelerator (version 2.5), which is integrated with a BrainLab ExacTrac imaging system (version 6.1.1). The phantom study was based on a Rando head phantom and was designed to evaluate isocenter location dependence of the image registrations. Ten isocenters at various locations representing clinical treatment sites were selected in the phantom. Cone-beam computed tomography and ExacTrac X-ray images were taken when the phantom was located at each isocenter. The patient study included 34 patients. Cone-beam computed tomography and ExacTrac X-ray images were taken at each patient’s treatment position. The 6 degree-of-freedom image registrations were performed on cone-beam computed tomography and ExacTrac, and residual errors calculated from cone-beam computed tomography and ExacTrac were compared. Results: In the phantom study, the average residual error differences (absolute values) between cone-beam computed tomography and ExacTrac image registrations were 0.17 ± 0.11 mm, 0.36 ± 0.20 mm, and 0.25 ± 0.11 mm in the vertical, longitudinal, and lateral directions, respectively. The average residual error differences in the rotation, roll, and pitch were 0.34° ± 0.08°, 0.13° ± 0.09°, and 0.12° ± 0.10°, respectively. In the patient study, the average residual error differences in the vertical, longitudinal, and lateral directions were 0.20 ± 0.16 mm, 0.30 ± 0.18 mm, 0.21 ± 0.18 mm, respectively. The average residual error differences in the rotation, roll, and pitch were 0.40°± 0.16°, 0.17° ± 0.13°, and 0.20° ± 0.14°, respectively. Overall, the average residual error differences were

Purpose Early stage lung cancer is treated with stereotactic body radiation therapy (SBRT) in patients who are unable or unwilling to undergo surgical resection. Some patients' comorbidities are so severe that they are unable to even undergo a biopsy. A clinical diagnosis without biopsy before SBRT has been used, but there are limited data on its efficacy. Methods and Materials Data on patients treated with SBRT for non-small cell lung cancer, with and without tissue confirmation, were collected from multiple institutions across Europe, Canada, and the United States. Patients with a minimum of 2 years of comprehensive follow up were selected for analysis. Treatment and patient characteristics were compared. Overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and rates of local recurrence (LR), regional recurrence (RR), and distant metastasis (DM) were calculated and analyzed. Results A total of 701 patients were identified, of which 67% had tissue confirmation of their tumors. The 3- and 5-year outcomes for OS, CSS, and DFS were 83.8%, 93.1%, 69%, and 60.6%, 86.7%, 45.5%, respectively. The rates for LR, RR, and DM at 3 and 5 years were 6.4%, 9.3%, 14.3%, and 10.5%, 14.3%, 19.7%, respectively. There were no statistically significant differences in survival outcomes or recurrences between the biopsy and no-biopsy cohorts. Conclusions SBRT for clinically diagnosed lung cancers is efficacious in appropriately selected patients, with similar outcomes as those with a pathologic diagnosis. Thorough clinical and radiographic evaluations in a multidisciplinary setting are critical to the management of these patients.

Stereotactic body radiation therapy has been associated with increased toxicity when delivered to patients with early-stage non-small cell lung cancer with a tumor within 2 cm of the proximal bronchial tree (PBT). We investigated noncancer deaths for these patients as related to gross tumor volume (GTV) proximity to the PBT, compared with peripheral tumors.We included 765 patients with early-stage non-small cell lung cancer who were treated with stereotactic body radiation therapy to a median of 3 × 18 Gy. Central tumors were treated with a risk-adapted (less-intense) schedule (mostly 8 fractions) in 55% of the patients in the first-centimeter group and 27% of the patients in the second-centimeter group. An average anatomy with contouring of PBT and organs at risk (OARs) was deformed onto each patient to obtain the distance of the GTV to the PBT and doses to OARs. Log-rank, 1-way analysis of variance, and Cox regressions were performed to assess differences in the first-centimeter, second centimeter, and peripheral groups and associations with noncancer deaths.The median overall survival was 42.7 months, the median noncancer death occurred in 57.3 months, and the median follow-up was 34.8 months. Noncancer death in the first-centimeter group (31 patients) was significantly different from noncancer death in the other groups, with a hazard ratio of 3.175 (P .001). Noncancer death in the second-centimeter group (71 patients) was not different from noncancer death in the peripheral group (P = .53). Doses to OARs were higher in the first- and second-centimeter groups than in the peripheral group for all OARs. High dose to the PBT was associated with noncancer death (D1%; hazard ratio, 1.006 GyPatients with a GTV in the first centimeter surrounding the PBT died more often from causes other than cancer compared with other patients. Noncancer death in patients with a GTV in the second centimeter, who partly received a risk-adapted schedule, was comparable to that in patients with a peripheral tumor.

2056 Background: Standard of care for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our clinical trial evaluating safety and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. Methods: This is a single arm pilot study. Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity of TTFields concurrent with chemoradiation in patients with newly diagnosed glioblastoma. Results: A total of 30 patients were enrolled in the trial. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). Median follow-up was 8.9 months (range 1.6 to 21.4 months). Twenty (66.7%) patients had unmethylated MGMT promotor status and ten (33.3%) patients had methylated promoter status. Median time from surgery to radiation was 34 days (26 to 49 days). Scalp dose constraints were achieved for all patients, with the mean dose having a median value of 8.3 Gy (range 4.3 to 14.8 Gy), the D20cc median was 26.1 Gy (range 17.7 to 42.8 Gy), and the D30cc median was 23.5 Gy (range 14.8 to 35.4 Gy). Skin adverse events (AEs; erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). Nineteen patients (63.3%) had progression, with a median PFS of 7.6 months (range 1.6 to 12.7 months). Overall survival was not reached. Conclusions: Concurrent TTFields (200 kHz) with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. Clinical trial information: NCT03477110.

Purpose Fibrotic changes after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) are difficult to distinguish from local recurrences (LR), hampering proper patient selection for salvage therapy. This study validates previously reported high-risk computed tomography (CT) features (HRFs) for detection of LR in an independent patient cohort. Methods and Materials From a multicenter database, 13 patients with biopsy-proven LR were matched 1:2 to 26 non-LR control patients based on dose, planning target volume (PTV), follow-up time, and lung lobe. Tested HRFs were enlarging opacity, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, linear margin disappearance, loss of air bronchogram, and craniocaudal growth. Additionally, 2 new features were analyzed: the occurrence of new unilateral pleural effusion, and growth based on relative volume, assessed by manual delineation. Results All HRFs were significantly associated with LR except for loss of air bronchogram. The best performing HRFs were bulging margin, linear margin disappearance, and craniocaudal growth. Receiver operating characteristic analysis of the number of HRFs to detect LR had an area under the curve (AUC) of 0.97 (95% confidence interval [CI] 0.9-1.0), which was identical to the performance described in the original report. The best compromise (closest to 100% sensitivity and specificity) was found at ≥4 HRFs, with a sensitivity of 92% and a specificity of 85%. A model consisting of only 2 HRFs, bulging margin and craniocaudal growth, resulted in a sensitivity of 85% and a specificity of 100%, with an AUC of 0.96 (95% CI 0.9-1.0) (HRFs ≥2). Pleural effusion and relative growth did not significantly improve the model. Conclusion We successfully validated CT-based HRFs for detection of LR after SBRT for early-stage NSCLC. As an alternative to number of HRFs, we propose a simplified model with the combination of the 2 best HRFs: bulging margin and craniocaudal growth, although validation is warranted.

An automatic brain‐metastases planning (ABMP) software has been installed in our institution. It is dedicated for treating multiple brain metastases with radiosurgery on linear accelerators (linacs) using a single‐setup isocenter with noncoplanar dynamic conformal arcs. This study is to validate the calculated absolute dose and dose distribution of ABMP. Three types of measurements were performed to validate the planning software: 1, dual micro ion chambers were used with an acrylic phantom to measure the absolute dose; 2, a 3D cylindrical phantom with dual diode array was used to evaluate 2D dose distribution and point dose for smaller targets; and 3, a 3D pseudo‐in vivo patient‐specific phantom filled with polymer gels was used to evaluate the accuracy of 3D dose distribution and radiation delivery. Micro chamber measurement of two targets (volumes of 1.2 cc and 0.9 cc, respectively) showed that the percentage differences of the absolute dose at both targets were less than 1%. Averaged GI passing rate of five different plans measured with the diode array phantom was above 98%, using criteria of 3% dose difference, 1 mm distance to agreement (DTA), and 10% low‐dose threshold. 3D gel phantom measurement results demonstrated a 3D displacement of nine targets of 0.7±0.4 mm (range 0.2 ~ 1.1 mm). The averaged two‐dimensional (2D) GI passing rate for several region of interests (ROI) on axial slices that encompass each one of the nine targets was above 98% (5% dose difference, 2 mm DTA, and 10% low‐dose threshold). Measured D95, the minimum dose that covers 95% of the target volume, of the nine targets was 0.7% less than the calculated D95. Three different types of dosimetric verification methods were used and proved the dose calculation of the new automatic brain metastases planning (ABMP) software was clinical acceptable. The 3D pseudo‐in vivo patient‐specific gel phantom test also served as an end‐to‐end test for validating not only the dose calculation, but the treatment delivery accuracy as well. PACS number(s): 87.53.Lv, 87.55.km, 87.55.Qr

Stereotactic body radiotherapy (SBRT) is the guideline-recommended treatment for medically inoperable patients with peripheral stage I non-small cell lung cancer (NSCLC). This study analyzed whether short-term (6 months) death can be predicted reliably to select a subgroup of patients who will not have a benefit from SBRT.A total of 779 patients with early-stage NSCLC who had been treated with cone beam computed tomography-guided SBRT in five institutes and for whom information on overall survival during the first 6 months after treatment was available were included in this analysis. The probability of dying within 6 months after treatment was defined as the end point "early death" and modeled by multivariate logistic regression. Model fitting was performed using the least absolute shrinkage and selection operator method, and model test performance was estimated using double 10-fold cross validation. The variables age, sex, Eastern Cooperative Oncology Group performance status, operability, forced expiratory volume in 1 second, and Charlson comorbidity index were considered for model building.Eastern Cooperative Oncology Group performance status and (to a lesser extent) operability were the most important predictors of early death, whereas the Charlson comorbidity index was associated only with the overall survival time. On the basis of the best expected test performance (area under the curve = 0.699), the risk for early death would be 8.8% (range 8.2%-13.7%) and 4.1% (3.0%-4.3%) for the 10% of patients with the highest and lowest risk, respectively. Overall, predictive performance was too low for clinical application.SBRT should be offered to all patients irrespective of their comorbidities, unless the performance status of the patients and the comorbidities prevent accurate SBRT planning and delivery.

Purpose This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life. Patients and Methods The phase I study increased TMZ doses from 100 to 150 to 200 mg/m2. Patients were treated with rituximab 375 mg/m2 3 days before cycle 1; methotrexate 3.5 g/m2 with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m2 daily for 5 days every 28 days on weeks 14 to 50. Results Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m2. Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT. Conclusion This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.

In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on (18)F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information.Patients with locally advanced NSCLC underwent (18)F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient's primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address overfitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan-Meier curves and log-rank testing were used to compare outcomes among patient groups.Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm(3), and the optimal SumMean cutpoint for tumors above 93.3 cm(3) was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P0.001).We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy. Validation studies are warranted.

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.

2501 Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .

9051 Background: Patients (pts) with resectable stage IB (≥4cm)-IIIA non-small-cell lung cancer (NSCLC) derive modest overall survival benefit with neoadjuvant or postoperative adjuvant chemotherapy. Neoadjuvant therapy can speed the discovery of promising regimens by using pathologic response as a surrogate for OS. Major pathologic response (MPR), defined as < 10% viable tumor, was strongly associated with improved OS. PD-(L)1 checkpoint inhibitors in combination with chemotherapy are standard of care in advanced NSCLC. We hypothesize that the addition of N to neoadjuvant CP or CG will increase the MPR rate compared to historical controls. Methods: This is an investigator-initiated trial for pts with newly diagnosed AJCC 8th stage IB (≥4cm)-IIIA squamous or non-squamous EGFR/ALK WT NSCLC with a plan to have surgery. Pts receive 3 courses of N 360mg IV q 3w added to C 75mg/m2 IV q 3w plus P 500 mg/m2 IV q 3wks or G 1250mg/m2 IV d1, d8 with surgery 3 wks after the last dose. The primary objective is MPR. To estimate pathologic response, the resected pathology specimens are cut >1 section/cm. Using the Aperio Digital scanning system©, slides were imaged, and then annotated by at least 2 pathologists for viable tumor vs. treatment effect with respective areas then automatically calculated and percentage of viable tumor calculated. Our primary endpoint will be reached if 10/34 (29%) planned pts have at least an MPR. Results: From 6/2018-8/2019, 13 pts were enrolled all of whom had surgery. Median age was 69 (49-80), 38% women, 31% nonsquamous, 54% stage IIIA, and 77% PD-L1 positive (≥1%, SP263). Pre-surgical grade 3 toxicity occurred in 2/13 pts, one of whom was changed to carboplatin for courses 2 and 3. Grade 3 toxicities were neutropenia (2/13), anemia (1/13), and renal (1/13). One pt. developed hypothyroidism 4 mos after surgery. One pt died 6 weeks after surgery from complications unrelated to study drugs. Our primary endpoint was met; 11/13 (85%), had at least an MPR with 6/13 (46%) and 5/13 (38%) having an MPR and pCR respectively. Radiologic response rate was 46% (PR 5, CR 1). Pts with either PD-L1+ or PD-L1- had MPRs. With a median follow-up of 10 months there are no recurrences. Conclusions: The combination of nivolumab added to platinum doublets was well tolerated. The primary endpoint of MPR in at least 10/34 pts was surpassed with MPR or pCR in 11/13 pts post-surgery. MPR was seen independent of PD-L1 score. Exploratory outcomes assessing markers of immune bias in tumor tissue and plasma are in process. Clinical trial information: NCT03366766.

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p

Introduction: We present a novel autologous cell vaccine therapy designed to treat patients with newly diagnosed glioblastoma (Trial Registration: IND 14379, NCT01550523). Methods: This phase 1b trial has a phase 2 design with 4 randomized vaccine dose cohorts in 33 patients with the objective being safety assessment but also including clinical, radiographic, and immune analyses. Eligibility criteria included age > 18 and Karnofsky score of > 60; neither bihemispheric disease nor extent of resection were exclusion criteria but autoimmune diseases were. During craniotomy for tumor resection, if frozen section confirmed GBM, incisions were made in the lower abdomen through the rectus sheath and pockets created between the sheath and the muscle and the wounds closed with a temporary three-layer closure. Tumor resection involved an aspirator that collected morselized viable tumor tissue in sterile traps. The tissue was processed by overnight culture with 0.2 mg of an IGF-1R antisense oligodeoxynucleotide/gm. The next (first postoperative) day, treated tumor cells were harvested, encapsulated in either ten or twenty small biodiffusion chambers along with 4 micrograms of the IGF-1R antisense, irradiated and then implanted at bedside in the abdominal acceptor sites as previously described (1). Chambers were explanted 24 or 48 hours later, depending on randomization. Standard of care according to Stupp (2) was initiated at 6 weeks. Studies included 3T MRI imaging and analysis of serial blood samples for T cell function and cytokine levels. Disease progression was assessed using RANO (3) and iRANO (4) criteria with a data cutoff of March 1 (N=30) used for this analysis. Results: The trial opened September 1, 2015 and completed accrual on March 1, 2018. A midpoint interim analysis revealed significantly more robust cytokine responses at the highest vaccine dose. Randomization was therefore stopped at subject 23 and amended to treat using only the highest dose. Progression-free survival (PFS) was compared to three historic SOC comparators (Stupp [2], Kong [5], and an antecedent cohort of 37 consecutive patients treated with SOC at our institution [TJUH]). PFS was significantly improved at 10.5 mo v. SOC comparators: 6.9 mo (Stupp, p = .003), 5.3 mo (Kong, p = .002) and 7 mo (TJUH, p = .013). Seventy-five percent of the 14 patients in the highest-dose cohort had robust proinflammatory and early evidence of sustained immune reactivity associated with tumor regression or no recurrence after surgery. Conclusion: These data reflect a therapeutic benefit defined as significant improvement in PFS without increased safety risk compared to three different SOC cohorts. Since GBM remains one of the most challenging solid tumors, this treatment design invites investigator collaboration in a multicenter phase 2 trial. References: 1. Andrew et al. J Clin Oncol 19:2189-2200; 2. Stupp et al. NEJM 352:987-96; 3. Wen et al. J Clin. Oncol 28:1963-72; 4. Okada et al. Lancet Oncol 16:534-42; 5. Kong et al. Oncotarget 8:7003-13. Citation Format: Kevin D. Judy, David W. Andrews, Larry Harshyne, Lawrence Kenyon, Kiran Talekar, Kofi-Buaku Atsina, Lyndon Kim, Wenyin Shi, Maria Werner-Wasik, Rhonda Kean, Samantha Garcia, Kara Pigott, Charles B. Scott, D. Craig Hooper. Phase 1b/2 prospective randomized trial of four autologous cell vaccine dose cohorts for initial treatment of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B71.

PURPOSE: To report the long-term outcomes and MGMT analysis of temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade gliomas (LGG) population. PATIENTS/ METHODS: For this single-arm phase II study, LGG patients with ≥3 risk factors (age ≥40, astrocytoma, bi-hemispheric tumor, size ≥6 cm or preoperative neurologic function status >1) received RT (54 Gy/30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The primary endpoint was overall survival (OS) at 3 years after registration. A one-sided Z-test was used to test the hazard rate based on the observed 3-year OS rate versus a prespecified historical control from the EORTC high-risk LGG population. Secondary endpoints included progression-free survival (PFS), and the association of survival outcomes with MGMT methylation status, for which the MGMT-STP27 prediction model was used based on 450k data. The initial report of this study was published in 2015, when the results of the MGMT analysis were unavailable. RESULTS: The study accrued 129 analyzable patients. The median follow-up for surviving patients was 9 years (range: 0.4–11.8), 4 years longer than previously reported. The 3-year OS rate was 73.5% (95% CI: 65.8–81.1%), superior to the historical control of 54% (p

Glioblastoma predominantly occurs in the 6th and 7th decades of life. The optimal treatment paradigm for elderly patients is not well established. We sampled current worldwide management strategies for elderly patients with newly diagnosed glioblastoma. A web-based survey was developed and distributed to 168 radiation oncologists, neuro-oncologists and neurosurgeons identified through the United Council for Neurologic Subspecialties and the CNS committees for North American, European and Asian Organizations. Questions addressed treatment recommendations in order to determine whether management consensus exists in this patient subset. There were 68 (40%) respondents. Across respondents, the most important factors directing treatment were KPS (94%) and MGMT methylation status (71%). Only 37% of respondents strictly factor in age when making treatment recommendations with 59% defining elderly as greater than 70 years-old. The most common treatment recommendations for MGMT-methylated elderly patients with KPS > 70 were as follows: standard chemoRT (49%), short course chemoRT (39%), and temozolomide alone (30%). The most common treatment recommendations for MGMT-unmethylated patients with KPS > 70 were as follows: short course RT alone (51%), standard chemoRT (38%), and short course chemoRT (28%). Treatment recommendations for patients with KPS

Introduction: Epidemiologic data indicate diabetes confers an augmented risk of lung cancer development, yet the relationship between hyperglycemia, metabolic agents, and prognosis is unclear. We analyzed the impact of hyperglycemia, anti-diabetic agents, and statins on outcomes in non-small cell lung cancer (NSCLC) patients undergoing chemoradiation. Method and Materials: In total, data from 170 patients with stage III NSCLC treated at the University of Pittsburgh Medical Center between 2001 and 2014 were obtained for analysis. Kaplan-Meier survival analysis was used to estimate time-to-event for overall survival (OS), disease-free survival, distant metastasis (DM), and loco-regional control (LRC). Blood glucose values (n = 2870), statins, and diabetic medications were assessed both continuously and categorically in univariable and multivariable Cox proportional hazard regression models to estimate hazard ratios and identify prognostic factors. Results: Tumor volume was a negative prognostic factor for OS, disease-free survival, DM, and LRC (p = 0.001). Tumor stage and treatment time were associated with increased all-cause mortality. Any glucose measurement ≥ 130 mg/dl during treatment (2-year estimate 49.9 vs. 65.8%, p = 0.095) was borderline significant for decreased LRC, with similar trends on multivariable analysis (HR 1.636, p = 0.126) and for OS (HR 1.476, p = 0.130). Statin usage was associated with improved 2-year LRC (53.4 vs. 62.4%, p = 0.088) but not with improvements in survival. Other glycemic parameters, comorbid diabetes diagnosis, or anti-diabetic medications were not significantly associated with outcomes. Conclusions: There were trends for blood glucose value over 130 mg/dl and statin nonuse being associated with inferior prognosis for LRC in stage III NSCLC patients; glycemic state, statin usage, and glucose-modulating medications were not associated with survival outcomes in multivariable analysis in this retrospective database.

Purpose To provide guidance to physicians and patients with regard to the use of adjuvant external beam radiation therapy (RT) in locally advanced non-small cell lung cancer (LA NSCLC) based on available medical evidence complemented by consensus-based expert opinion. Methods and materials A panel authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors and Guidelines Subcommittee conducted 2 systematic reviews on the following topics: (1) indications for postoperative adjuvant RT and (2) indications for preoperative neoadjuvant RT. Practice guideline recommendations were approved using an a priori–defined consensus-building methodology supported by ASTRO and approved tools for the grading of evidence quality and the strength of guideline recommendations. Results For patients who have undergone surgical resection, high-level evidence suggests that use of postoperative RT does not influence survival, but optimizes local control for patients with N2 involvement, and its use in the setting of positive margins or gross primary/nodal residual disease is recommended. No high-level evidence exists for the routine use of preoperative induction chemoradiation therapy; however, modern surgical series and a post-hoc Intergroup 0139 clinical trial analysis suggest that a survival benefit may exist if patients are properly selected and surgical techniques/postoperative care is optimized. Conclusions A consensus and evidence-based clinical practice guideline for the adjuvant radiotherapeutic management of LA NSCLC has been created addressing 2 important questions.

Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power.Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ.From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis.The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P.001) and the study-hypothesized rate of 65%.

Incidental radiation dose to the heart and lung during breast radiation therapy (RT) has been associated with an increased risk of cardiopulmonary morbidity. We conducted a prospective trial to determine if RT with the Active Breathing Coordinator (ABC) can reduce the mean heart dose (MHD) by ≥20% and dose to the lung.Patients with stages 0-III left breast cancer (LBC) were enrolled and underwent simulation with both free breathing (FB) and ABC for comparison of dosimetry. ABC was used during the patient's RT course if the MHD was reduced by ≥5%. The median prescription dose was 50.4 Gy plus a boost in 77 patients (90%). The primary endpoint was the magnitude of MHD reduction when comparing ABC to FB. Secondary endpoints included dose reduction to the heart and lung, procedural success rate, and adverse events.A total of 112 patients with LBC were enrolled from 2002 to 2011 and 86 eligible patients underwent both FB and ABC simulation. Ultimately, 81 patients received RT using ABC, corresponding to 72% procedural success. The primary endpoint was achieved as use of ABC reduced MHD by 20% or greater in 88% of patients (P.0001). The median values for absolute and relative reduction in MHD were 1.7 Gy and 62%, respectively. RT with ABC provided a statistically significant dose reduction to the left lung. After a median follow up of 81 months, 8-year estimates of locoregional relapse, disease-free, and overall survival were 7%, 90%, and 96%, respectively.ABC was well tolerated and significantly reduced MHD while preserving local control. Use of the ABC device during RT should be considered to reduce the risk of ischemic heart disease in populations at risk.

Background This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

The management of brain metastases involves either definitive or post-operative whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). While radiation improves intracranial control, it is unclear whether this response is dependent on tumor type. We therefore performed a single institution, retrospective analysis of 52 patients with Stage IV renal cell carcinoma (RCC) with metastatic brain lesions who were treated with either WBRT or SRS between 1995 and 2016. Overall survival was defined as time from completion of radiation therapy until death of any cause. Univariate analysis was performed using the Kaplan Meier method, and differences between the groups was assessed with the log-rank test. The median age was 59 and 52.5 in the WBRT and SRS groups, respectively. The median RPA for both groups was 2. For both WBRT and SRS the average number of treated brain lesions was 3. The median dose of WBRT was 3750 cGy while the median dose delivered via SRS was 2100 cGy. The median overall survival of patients receiving SRS was 11.9 months while those receiving WBRT was 15 months (HR 1.14 95% CI 0.58 to 2.23). Progression free survival was 6.23 months and 7.5 months for SRS and WBRT, respectively (HR 1.55, 95% CI 0.78 to 3.05). While intracranial progression was delayed in those treated with WBRT, this difference was not significant (HR 0.56 CI 95% 0.19 to 1.61). 28% of patients who were treated with WBRT ultimately received salvage SRS, and 17% of those who received upfront SRS ultimately received salvage WBRT. From these data, we conclude that both WBRT and SRS remain viable options for the treatment of brain metastases in patients with metastatic renal cell carcinoma. While there was a numerical improvement in median overall survival, progression free survival, and intracranial progression, these findings were not significant.

OBJECTIVEThis is the first clinical outcomes report of NRG Oncology RTOG 0539, detailing the primary endpoint, 3-year progression-free survival (PFS), compared with a predefined historical control for intermediate-risk meningioma, and secondarily evaluating overall survival (OS), local failure, and prospectively scored adverse events (AEs).METHODSNRG Oncology RTOG 0539 was a Phase II clinical trial allocating meningioma patients to 1 of 3 prognostic groups and management strategies according to WHO grade, recurrence status, and resection extent. For the intermediate-risk group (Group 2), eligible patients had either newly diagnosed WHO Grade II meningioma that had been treated with gross-total resection (GTR; Simpson Grades I–III) or recurrent WHO Grade I meningioma with any resection extent. Pathology and imaging were centrally reviewed. Patients were treated with radiation therapy (RT), either intensity modulated (IMRT) or 3D conformal (3DCRT), 54 Gy in 30 fractions. The RT target volume was defined as the tumor bed and any nodular enhancement (e.g., in patients with recurrent WHO Grade I tumors) with a minimum 8-mm and maximum 15-mm margin, depending on tumor location and setup reproducibility of the RT method. The primary endpoint was 3-year PFS. Results were compared with historical controls (3-year PFS: 70% following GTR alone and 90% with GTR + RT). AEs were scored using NCI Common Toxicity Criteria.RESULTSFifty-six patients enrolled in the intermediate-risk group, of whom 3 were ineligible and 1 did not receive RT. Of the 52 patients who received protocol therapy, 4 withdrew without a recurrence before 3 years leaving 48 patients evaluable for the primary endpoint, 3-year PFS, which was actuarially 93.8% (p = 0.0003). Within 3 years, 3 patients experienced events affecting PFS: 1 patient with a WHO Grade II tumor died of the disease, 1 patient with a WHO Grade II tumor had disease progression but remained alive, and 1 patient with recurrent WHO Grade I meningioma died of undetermined cause without tumor progression. The 3-year actuarial local failure rate was 4.1%, and the 3-year OS rate was 96%. After 3 years, progression occurred in 2 additional patients: 1 patient with recurrent WHO Grade I meningioma and 1 patient with WHO Grade II disease; both remain alive. Among 52 evaluable patients who received protocol treatment, 36 (69.2%) had WHO Grade II tumors and underwent GTR, and 16 (30.8%) had recurrent WHO Grade I tumors. There was no significant difference in PFS between these subgroups (p = 0.52, HR 0.56, 95% CI 0.09–3.35), validating their consolidation. Of the 52 evaluable patients, 44 (84.6%) received IMRT, and 50 (96.2%) were treated per protocol or with acceptable variation. AEs (definitely, probably, or possibly related to protocol treatment) were limited to Grade 1 or 2, with no reported Grade 3 events.CONCLUSIONSThis is the first clinical outcomes report from NRG Oncology RTOG 0539. Patients with intermediate-risk meningioma treated with RT had excellent 3-year PFS, with a low rate of local failure and a low risk of AEs. These results support the use of postoperative RT for newly diagnosed gross-totally resected WHO Grade II or recurrent WHO Grade I meningioma irrespective of resection extent. They also document minimal toxicity and high rates of tumor control with IMRT.Clinical trial registration no.: NCT00895622 (clinicaltrials.gov).

For patients with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC), concurrent chemoradiotherapy improves overall survival as compared to sequential chemotherapy and radiation therapy, but is associated with higher rates of toxicities. Acute, clinically significant esophagitis or pneumonitis can occur in one in five patients. The risks of esophagitis and pneumonitis can impact the decision to deliver concurrent therapy and limit the total dose of radiation therapy that is delivered. Hematologic toxicities and emesis are common toxicities from systemic therapies for LA-NSCLC and can result in delaying chemotherapy dosing or chemotherapy dose reductions. Late treatment morbidities, including pulmonary fibrosis and cardiac toxicities, can also significantly impact quality of life and potentially even survival. Recent advances in radiation therapy treatment delivery, better knowledge of normal tissue radiotherapy tolerances and more widespread and improved uses of supportive care and medical management of systemic therapy toxicities have improved the therapeutic ratio and reduced the rates of chemoradiotherapy-induced toxicities. This review details the acute and late toxicities associated with definitive chemoradiotherapy for LA-NSCLC and discusses toxicity management and strategies to mitigate the risks of treatment-related toxicities.

Introduction NRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC. Methods Patients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required. Results A total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT ( p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT. Conclusions OS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.

Purpose European data suggest that 8-fraction stereotactic body radiation therapy (SBRT) regimens may be similar in efficacy with less toxicity than ≤5-fraction SBRT for central lung lesions. However, under current Centers for Medicare and Medicaid Services guidelines, SBRT in the United States (US) is reimbursed for only ≤5 fractions, whereas there are no such restrictions for reimbursement in Canada. We hypothesize that US-specific SBRT reimbursement policies influence the use of ≥5-fraction SBRT in US academic centers in comparison with comparable Canadian centers. Methods and Materials A 15-question electronic survey was distributed to radiation oncologists at National Cancer Institute–designated cancer centers in the US and the 10 highest research-funded cancer centers in Canada. Fisher exact test or exact logistic regression if applicable was used, where P Results Of the 143 radiation oncologists from 60 US cancer centers and 6 Canadian cancer centers who completed the survey (17.6% response rate), 125 routinely prescribe SBRT. Fifty percent of US physicians versus 0% of Canadian physicians indicated that there are instances when they would like to prescribe >5-fraction SBRT but prescribe ≤5 fractions because of insurance reimbursement (P=.076 and P=.001, respectively). Seventy percent (P=.006) of US radiation oncologists versus 0% (P=.001) of Canadian radiation oncologists report that SBRT clinical investigation is constrained by the insurance reimbursement. The most common reported deterrent to prescribing >5-fraction SBRT in the US was insurance reimbursement (49.5%). Conclusions US radiation oncologists are more likely than those in Canada to report that SBRT clinical investigation and >5-fraction SBRT use may be negatively influenced by health insurance reimbursement; this perception was not held by physicians in Canada. Health care environment may significantly affect radiation therapy decision making and practice patterns.

Background The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Methods Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Results Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). Conclusions RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.

Purpose: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool ( (brainmetgpa.com)) simplified GPA use. Results: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the numbermore » of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.« less

Background Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. Methods In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary ...

Purpose: To determine the precision of our institution’s current immobilization devices for spine SBRT, ultimately leading to recommendations for appropriate planning margins. Methods: We identified 12 patients (25 treatments) with spinal metastasis treated with spine Stereotactic Body Radiation Therapy (SBRT). The Body-FIX system was used as immobilization device for thoracic (T) and lumbar (L) spine lesions. The head and shoulder mask system was used as immobilization device for cervical (C) spine lesions. Initial patient setup used the infrared positioning system with body markers. Stereotactic X-ray imaging was then performed and correction was made if the initial setup error exceeded predetermined institutional tolerances, 1.5 mm for translation and 2° for rotation. Three additional sets of verification X-rays were obtained pre-, mid-, and post-treatment for all treatments. Results: Intrafraction motion regardless of immobilization technique was found to be 1.28 ± 0.57 mm. The mean and standard deviation of the variances along each direction were as follows: Superior-inferior, 0.56 ± 0.39 mm and 0.77 ± 0.52 mm, (p = 0.25); Anterior-posterior, 0.57 ± 0.43 mm and 1.14 ± 0.61 mm, (p = 0.01); Left-right, 0.48 ± 0.34 mm and 0.74 ± 0.40 mm, (p = 0.09) respectively. There was a significantly greater difference in the average 3D variance of the BodyFIX as compared to the head and shoulder mask immobilization system, 1.04 ± 0.46 mm and 1.71 ± 0.52 mm; (p = 0.003) respectively. Conclusions: Overall, our institution’s image guidance system using stereotactic X-ray imaging verification provides acceptable localization accuracy as previously defined in the literature. We observed a greater intrafraction motion for the head and shoulder mask as compared with the BodyFIX immobilization system, which may be a result of greater C-spine mobility and/or the suboptimal mask immobilization. Thus, better immobilization techniques for C-spine SBRT are needed to reduce setup error and intrafraction motion. We are currently exploring alternative C-spine immobilization techniques to improve set up accuracy and decrease intrafraction motion during treatment.

BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

INTRODUCTION Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with electric tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-preserving radiation with concurrent TTFields. METHODS We conducted a single arm pilot study. Adult patients (≥ 18 years old) with KPS ≥ 60 with newly diagnosed glioblastoma were included. All patients received concurrent scalp-preserving radiation (60 Gy in 30 fractions), standard temozolomide (75 mg/m2 daily), and TTFields (200 kHz; ≥ 18 hr daily). Maintenance therapy included standard temozolomide and TTFields. Radiation treatment was delivered through TTFields arrays. Our primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. RESULTS Here we report the first seven patients on the trial. Five were male, and 2 female, with median age 58 y/o (range 49–73). Median KPS was 90. Median follow-up was 5.2 months (range 1.4–11.2). MGMT status was unmethylated for 6 patients, and one unknown, and no IDH mutations. Four (57.1%) received gross total resection and three (42.9%) had subtotal resection. All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. There was no related Grade 3 or higher toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in all patients, however, limited to Grade 1 or 2 which resolved spontaneously or responded to topical medications. All patients were alive at time of writing. Two (28.6%) patients had progression, of which one (at 9 months) continued TTFields and temozolomide with bevacizumab, while the other (at 4 months) discontinued TTFields and underwent re-resection with bevacizumab. CONCLUSIONS Concurrent TTFields with scalp-preserving chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

Background: We evaluated an autologous cell vaccine, a combination of GBM tumor cells and an antisense molecule against insulin-like growth factor type 1 receptor DNA/mRNA (IGF-1R AS ODN), in adults with newly diagnosed GBM (NCT02507583). Methods: Tumor cells collected during resection were treated ex vivo with IGF-1R AS ODN, encapsulated in biodiffusion chambers with IGF-1R AS ODN, irradiated, then implanted in an abdominal acceptor site on the first post-operative day. Four vaccine exposures were evaluated: lowest (10 chambers implanted for 24 hours); lower (10 / 48 hours); higher (20 / 24 hours); and highest (20 / 48 hours). Standard of care (SOC; ie, radiotherapy and temozolomide) was initiated after 4-6 weeks. Randomization was halted after patient 23 and subsequent patients received the highest exposure. Evaluation of safety and tumor responses were the primary and secondary objectives, respectively. Exploratory objectives included assessment of progression-free survival (PFS) and overall survival (OS). The SOC comparator group was an antecedent cohort of 35 newly diagnosed, GBM patients treated at the same center. Results: Thirty-three patients were enrolled between September 1, 2015 and March 1, 2018. Six, 5, 5, and 17 patients received the lowest, lower, higher, and highest exposures. Median (range) follow-up was 13 (4-39) months. As of the January 1, 2019 cutoff, no vaccine-related adverse events were observed. Seventeen of 33 (51.5%) remained progression-free, 12 of whom are alive and functioning well. The autologous cell vaccine significantly prolonged PFS and OS vs. SOC (Table). Survival advantages were conferred by the highest exposure to the autologous cell vaccine and good T cell function prior to surgery. Conclusions: This vaccine was well-tolerated and prolonged PFS and OS when compared with SOC alone. Table.Survival outcomes in patients receiving vaccine vs. SOC aloneTreatment group2 yr OS estimateMedian OS (mo)p-value v. SOC for OS1 yr PFS estimateMedian PFS estimatep-value v. SOC for PFSVaccine highest dose (N=17)34%21.9.04141%10.4.031Vaccine all (ITT, N=33)31%17.3.01642%9.8.018SOC (n=35)14%12.128%6.9 Citation Format: David W. Andrews, Samantha Garcia, Kevin D. Judy, Larry A. Harshyne, Sanjana Govindarajan, Lawrence Kenyon, Kiran Talekar, Adam Flanders, Kofi-Buaku Atsina, Lyndon Kim, Nina L. Martinez, Wenyin Shi, Maria Werner-Wasik, Mikhail Prosniak, Mark T. Curtis, Rhonda Kean, Emily Bongiorno, Sami Sauma, Kara Pigott, Charles B. Scott, D Craig Hooper. Results of a Phase Ib trial of an autologous cell vaccine for newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT038.