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PDF File - 501K, PF02341066 is well tolerated in female athymic nude mice.

PDF File - 57K, Legends for Supplementary Figures 1-3.

Purpose:Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.Patients and Methods:This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.Results:Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted.Conclusions:IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Determination of severity for adverse events

Pan-Cancer Immunity Panel for advanced analysis of T cell activation scores

Background/purpose Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here—https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/.

Four-dimensional computed tomography (4DCT)-ventilation-based functional avoidance uses 4DCT images to generate plans that avoid functional regions of the lung with the goal of reducing pulmonary toxic effects. A phase 2, multicenter, prospective study was completed to evaluate 4DCT-ventilation functional avoidance radiation therapy. The purpose of this study was to report the results for pretreatment to posttreatment pulmonary function test (PFT) changes for patients treated with functional avoidance radiation therapy.Patients with locally advanced lung cancer receiving chemoradiation were accrued. Functional avoidance plans based on 4DCT-ventilation images were generated. PFTs were obtained at baseline and 3 months after chemoradiation. Differences for PFT metrics are reported, including diffusing capacity for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEVFifty-six patients enrolled on the study had baseline and posttreatment PFTs evaluable for analysis. The mean change in DLCO, FEVThe current work is the first to quantitatively characterize PFT changes for patients with lung cancer treated on a prospective functional avoidance radiation therapy study. In comparison with patients treated with standard thoracic radiation planning, the data qualitatively show that functional avoidance resulted in less of a decline in DLCO and FEV

Background Virtually all patients with medically inoperable stage I non-small cell lung cancer (NSCLC) can receive stereotactic body radiation therapy. However, the percentage of such patients in whom sublobar resection is technically feasible is unknown. This discrepancy can confound clinical trial eligibility and designs comparing stereotactic body radiation therapy vs. sublobar resection. Methods A total of 137 patients treated with stereotactic body radiation therapy for lung lesions (3/2013-11/2017) underwent retrospective review. Diagnostic CT chest and PET/CT images, stereotactic body radiation therapy dates, and demographic data were collected on 100 of 137 patients. Two experienced board-certified thoracic surgeons independently reviewed anonymized patients' pre-stereotactic body radiation therapy diagnostic imaging and completed a custom survey about the technical feasibility of sublobar resection for each patient. Interrater agreement was measured using Cohen's kappa coefficient by bootstrap methodology. Summary statistics were performed for baseline demographics and tumor characteristics. Results Of the 100 patients, 57% were female, with median age of 75 years (range, 52-95 years) and Karnofsky Performance Status of 80 (range, 40-100). Most patients (61%) had Stage IA1, T1a tumors. For interrater agreement analysis, one patient was removed from each cohort due to inability to locate tumor on images, leaving 98 patients analyzed. Comparing Surgeon #1 vs. Surgeon #2, 64 (65.3%) vs. 69 (70.3%) of tumors were thought eligible for sublobar resection, respectively (κ=0.414). Conclusions Stereotactic body radiation therapy for stage I NSCLC is applicable to more tumors than sublobar resection, with ~30-35% of stereotactic body radiation therapy patients unable to undergo sublobar resection assessed by pretreatment diagnostic imaging based on technical grounds. This study illustrates that clinical trials comparing stereotactic body radiation therapy vs. sublobar resection are limited to only a subpopulation of patients with stage I NSCLC.

Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas. The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion. Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002). WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%−81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6–9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with 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-sparing radiation with concurrent TTFields. This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m2 daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70–90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months). Concurrent TTFields with scalp-sparing 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. Clinicaltrials.gov Identifier NCT03477110

Background High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data. Materials and methods We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size. Results A total of 109 local progressions were observed after a median of 17.7 months (range 0.6–76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12–16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy. Conclusions Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12–16 Gy are more probable, consistent with recent meta-regression analyses.

PURPOSE/OBJECTIVE(S) Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) along with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. Secondary analysis of EF14 trial demonstrated TTFields treatment may increase the rate of distant recurrence. We report our experience evaluating areas of progression in our pilot clinical trial of concurrent chemoradiation with TTFields. MATERIALS/METHODS This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from primary enhancing lesion. RESULTS A total of 30 patients were enrolled on the trial. Twenty were male, and ten were female, with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 8.9 months (1.6-21.4 months). Twenty (66.7%) patients had an unmethylated MGMT promotor status and ten (33.3%) patients had a methylated promoter status. Nineteen patients (63.3%) had progression, with median PFS of 7.6 months (range 1.6 to 12.7 months). Five patients (26%) of patient presented with distant recurrence, with median distance from primary lesion of 5.1 cm (2.26-9.12 cm). No distant infratentorial progression was noted. CONCLUSION Concurrent chemoradiation with TTFields for patients with newly diagnosed glioblastoma may increase the incidence of distant recurrence. This finding is suggestive of improved local control of primary site. Further data are needed to validate this finding. AUTHOR DISCLOSURE A. Ali: None. M.Z. Niazi: None. V. Bar-Ad: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. D.W. Andrews: None. C. Farrell: None. J. Evans: None. K. Judy: None. J. Glass: None. N. Martinez: None. I. Alnahhas: None. I. Chervoneva: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, Brainlab, Regeneron. Consultant; Varian, Brainlab, Zai lab.

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

Purpose The digitization of healthcare for patient safety and efficiency introduced third party networks into closed hospital systems increasing the probability of cyberattacks and their consequences(1). In April 2021, a major vendor of a Radiation Oncology (RO) record and verify system (RVS) suffered a ransomware attack, affecting our department and many others across the United States. This article summarizes our response to the ransomware event including workflows, team member roles, responsibilities, communications and departmental recovery. Methods and Materials The RVS created or housed accurate patient dose records for 6 locations. The immediate response to the ransomware attack was to shut down the system including the ability to treat patients. With the utilization of the hospital EMR and pre-existing interfaces with RVS, the department was able to safely continue patient radiotherapy treatments innovatively utilizing a direct DICOM transfer of patient data to the linear accelerators and implementing paper charting. Human capital costs included communication, outreach, workflow creation, quality assurance and extended clinical hours. Results No patients were treated in the first 24 hours of the attack. Within 48 hours of the ransomware event, 50% of patients were treated, and within 1 week, 95% of all patients were treated using direct DICOM transfer and paper charts. The RVS was completely unavailable for 2.5 weeks and full functionality was not restored for 4.5 weeks. A phased approach was adopted for re-introduction of patient treatments back into the RVS. Conclusions Key lessons learned were to have a back-up of essential information, employ ‘dry run' emergency training, having consistent parameter requirements across different vendor hardware and software, and having a plan for the recovery effort of restoring normal operations once software is operational. The provided report presents valuable information for the development of cyber-attack preparedness for RO departments.

In a previous study of smoking cessation in veterans with lung cancer, we noted as an incidental finding that current smokers were much younger than former smokers at diagnosis. To confirm and extend this observation, we analyzed the association of smoking status with age at diagnosis and survival of lung cancer patients. The Jefferson Cancer Registry collects information on all cancer patients registered at this hospital. Information on smoking status has been recorded since 1995. We determined age at diagnosis and survival of current and former smokers with lung cancer. 5111 lung cancer cases were identified in the registry from 1995 to 2011 inclusive. Smoking status was recorded in 4687 cases (91.7%). Of these, 1859 (39.7%) were current, 2423 (51.7%) were former, and 405 (8.6%) were never smokers. There was a 6-year difference in median age at lung cancer diagnosis between the current (63 years) and former smokers (69 years) (P

Background and purpose We conducted a phase I trial of alisertib, an oral aurora kinase inhibitor, with fractionated stereotactic re-irradiation therapy (FSRT) for patients with recurrent high grade glioma (HGG). Materials and methods Adult patients with recurrent HGG were enrolled from Feb 2015 to Feb 2017. Patients were treated with concurrent FSRT and alisertib followed by maintenance alisertib. Concurrent alisertib dose was escalated from 20 mg to 50 mg twice daily (BID). Results 17 patients were enrolled. Median follow-up was 11 months. Median FSRT dose was 35 Gy. There were 6, 6, 3, and 2 patients enrolled in 20 mg, 30 mg, 40 mg, and 50 mg cohort, respectively. Only one DLT was observed. One patient in the 20 mg cohort had severe headache (Grade 3) resolved with steroids. There was no non-hematological grade 3 or higher toxicity. There were two Grade 4 late toxicities (one with grade 4 neutropenia and leukopenia, one with pulmonary embolism). One patient developed radiation necrosis (Grade 3). Sixteen patients finished concurrent treatment and received maintenance therapy (median cycles was 3, range 1–9). OS for all cohorts at 6 months was 88.2% with median survival time of 11.1 months. PFS at 6 months was 35.3% with median time to progression of 4.9 months. The trial stopped early due to closure of alisertib program with only 2 of 3 planned patients enrolled in the 50 mg cohort. Conclusion Re-irradiation with FSRT combined with alisertib is safe and well tolerated for HGG with doses up to 40 mg BID. Although no DLT observed in the 50 mg cohort, this cohort was not fully enrolled and MTD was not reached. Clinical outcomes appear comparable to historical results. (NCT02186509)

INTRODUCTION Current adjuvant treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. METHODS Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with 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 tri-modality treatment within 30 days of completion of chemoradiation treatment. RESULTS Thirty patients were enrolled. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median follow-up was 10.8 months (range 1.6 to 21.3 months). Twenty (66.7%) patients had unmethylated MGMT promotor and ten (33.3%) patients had methylated promoter. Scalp dose constraints were achieved for all patients. Skin adverse events (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%). The median PFS for the entire cohort was 9.1 months (at least 8.5 months, 95% confidence). The median PFS for patients with MGMT promoter methylation status was 11.4 months (at least 9.5 months, 95% confidence). Overall survival was not reached. CONCLUSIONS Concurrent TTFields with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

PURPOSE/OBJECTIVE(S) Current treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields, 200 kHz). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. MATERIALS/METHODS This is a single arm pilot study. Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with 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. Total scalp was defined as 5 mm thickness from skin surface above the level of the foramen magnum. The scalp was used as an avoidance structure for planning, with the following dose constraints: mean < 20 Gy, 20 cc < 50 Gy, and 30 cc < 40 Gy. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. 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. CONCLUSION Concurrent TTFields (200 kHz) with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. AUTHOR DISCLOSURE R.C. Miller: None. A.J. Song: None. A. Ali: None. V. Bar-Ad: None. N. Martinez: None. J. Glass: None. I. Alnahhas: None. D.W. Andrews: None. K. Judy: None. J. Evans: None. C. Farrell: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. I. Chervoneva: None. M. Ly: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.H. Liu: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, BrainLab, Regeneron. Consultant; Varian, BrainLab, Zai lab.

PURPOSE/OBJECTIVE(S) To evaluate the clinical role of temozolomide rechallenge (TMZ) in patients with recurrent high-grade glioma (HGG) treated with re-irradiation (re-RT) regardless of surgical status. MATERIALS/METHODS Single-center retrospective review of patients with a primary diagnosis of World Health Organization (WHO) Grade III anaplastic astrocytoma or Grade IV GBM treated from 2008 to 2016 for disease recurrence with re-RT (35 Gy in 10 fractions) with and without temozolomide rechallenge. Baseline characteristics were analyzed with pairwise tests. OS/PFS were assessed with the Kaplan-Meier method and multivariable cox regression models for OS. RESULTS Two hundred and thirty patients were treated with re-irradiation (n = 67 with and n = 163 without concurrent TMZ), with a median follow-up of 13.4 months. Baseline characteristics were similar between the two groups. TMZ rechallenge did not improve OS (HR 0.81 [0.51-1.3] P = 0.39). Univariate regression analysis showed that higher KPS both at diagnosis and recurrence correlated with improved survival, whereas increasing histology grade of initial and recurrent disease and volume of recurrence were correlated with worse OS. Multivariate regression analysis showed primary tumor location to be a significant predictor of OS (P = 0.004) with occipital lobe lesions (P < 0.001) and in-field recurrence (P < 0.001) to be most favorably correlated with OS. CONCLUSION TMZ rechallenge in patients with recurrent HGG treated with re-irradiation offered no survival benefit. Our findings suggest that patient selection may be important in TMZ rechallenge. Further studies in identifying this group of patients are warranted. AUTHOR DISCLOSURE M.M. Basree: None. A. Ali: None. S. Garg: None. J. Glass: None. L. Kim: None. C. Farrell: None. J. Evans: None. K. Judy: None. D.W. Andrews: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, Brainlab, Regeneron. Consultant; Varian, Brainlab, Zai lab. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.

8513 Background: In advanced non-small cell lung cancer (NSCLC), high Programmed-Death-1 Ligand (PD-L1) (>50%) expression demonstrate superior response and survival with immune checkpoint inhibitors compared to chemotherapy. We hypothesize that it is safe and feasible to substitute durvalumab instead of chemotherapy concurrently with radiotherapy (RT) in patients with Locally Advanced-NSCLC (LA-NSCLC) and high PD-L1. Methods: NRG-LU004 (NCT03801902) is a Phase I study for patients with stage II-III unresectable or inoperable, LA-NSCLC with PD-L1> 50% (Dako 22C3 or Ventana SP263) expression. There were safety and expansion phases with a primary endpoint of safety. Patients started with 1500 mg durvalumab Q4 weeks and thoracic RT within 2 weeks from 1st infusion. Durvalumab continued once a month up to 1 year. In the safety cohort, 6 patients in cohort 1 were treated with accelerated fractionated RT (ACRT) to 60 Gy in 15 fractions, followed by a required safety hold for 90 days. During cohort 1 safety hold, cohort 2 patients were treated with conventional RT 60 Gy in 30 fractions (CONV) followed by a 60-day safety hold. A cohort advanced to the expansion phase to enroll 6 more patients if safety criteria (0-1 patients with a dose limiting toxicity [DLT]) were met. If both cohorts were deemed safe, patients would be randomized 1:1 to ACRT or CONV with safety defined as < 4 of 12 evaluable patients per arm experiencing a DLT. Feasibility was defined as at least 80% of patients in each arm receiving at least 80% of the planned dose of durvalumab during the first 8 weeks. Results: 24 evaluable patients enrolled between January 2019 and June 2021. No DLTs were reported in cohort 1, and 1 (unrelated bronchopulmonary hemorrhage leading to discontinuation of durvalumab) in cohort 2. Both safety cohorts advanced to the expansion phase. All but one patient (CONV) received RT per protocol/with an acceptable variation. At the time of analysis, 24% had received all 13 cycles of durvalumab. For the ACRT cohort, there were 4 grade 3, 1 grade 4 (lymphopenia), and 1 grade 5 AE (lung infection, assessed as unrelated to therapy). For CONV, there were 8 grade 3, 0 grade 4, and 1 grade 5 AE (respiratory failure, unrelated to therapy). For feasibility, 10 of 12 (85%) patients in the ACRT cohort received the second dose of durvalumab (2 not received due to shingles and unrelated death), while 9 of 12 (75%) of the CONV cohort received the second dose (reasons for not receiving: viral hepatitis, bronchopulmonary hemorrhage, and respiratory failure, all assessed as unrelated to therapy). Conclusions: Chemotherapy-free thoracic RT approaches (ACRT or CONV RT) are safe, when given with concurrent durvalumab in patients with PD-L1 high LA-NSCLC. A trial to compare immunoradiotherapy and consolidation durvalumab to standard chemoradiation and consolidation durvalumab is planned. Clinical trial information: NCT03801902.

Meningeal melanocytomas are rare, benign tumours of the central nervous system arising from the melanocytes of the leptomeninges. First-line treatment consists of either gross or subtotal resection with or without radiotherapy. However, given the sensitive locations of these tumours, alternative treatment options such as definitive radiotherapy may be warranted in patients deemed high-risk or without accessible tumours. A 67-year-old male presenting with spastic gait, frequent falls, and vertical gaze palsy was diagnosed with a 2.4 cm primary meningeal melanocytoma arising from the interpeduncular fossa. Given the critical tumour position within the brainstem, definitive radiotherapy was recommended. He received fractionated stereotactic radiotherapy (FSRT) to a total dose of 54 Gy in 27 fractions, resulting in a gradual improvement in gait and ocular range of motion. Follow-up imaging over the next three years revealed largely stable disease and an increase in edema with mild upper extremity weakness that improved with steroids. He was followed for three years and expired four years after treatment due to pneumonia. For patients unable to receive surgical resection, definitive RT may provide local control with minimal morbidity.

INTRODUCTION Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide (TMZ) with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report our experience evaluating toxicity of scalp-sparing radiation with concurrent TTFields. METHODS This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Patients (age≥ 18 years) with KPS≥ 60 with newly diagnosed glioblastoma were eligible. Patients received concurrent scalp-sparing radiation (60 Gy/30 fx), standard TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and TTFields continuation. Radiotherapy was delivered through TTFields arrays. Primary endpoint was safety and toxicity of concurrent TTFields with chemoradiation. RESULTS We report the first eighteen patients on trial. Majority were male (66.7%) with median age 59 years (34 to 77). Median KPS was 90 (70–100). Median follow-up was 6.0 months (1.4 to 18.0). Twelve (66.6%) patients had unmethylated MGMT, five (27.8%) were methylated, and one patient’s status was not obtained. Scalp dose constraints were achieved, with mean dose having a median value of 7.4 Gy (4.3–13.2), D20cc median 23.2 Gy (17.7–36.8), and D30cc median 20.3 Gy (14.8–33.4). Only one possible Grade 3 toxicity was observed in a patient who experienced a seizure in month six of the maintenance phase. Skin toxicity (erythema or dermatitis) was limited to Grade 1 (83.3%) or 2 (5.6%) during the concurrent phase and resolved spontaneously or responded to topical medications. Other Grade 1 events included fatigue (47.3%), cognitive impairment (31.6%), pruritis (52.6%), headache (26.3%), dizziness (15.8%), and nausea (26.3%). Other Grade 2 events included fatigue (21.1%) and headache (10.5%). Nine patients (50%) had progression, with median PFS of 7.6 months (2.2–9.6 months). CONCLUSIONS Concurrent TTFields 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.

Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas.The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion.Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs.5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002).WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.

Background Sarcopenia has been associated with poor survival among cancer patients. Normalized total psoas area (NTPA) has been used as a surrogate for defining sarcopenia. Few data exist characterizing the impact of sarcopenia and other metrics of fitness on clinical outcomes in patients with early-stage non-small cell lung cancer (NSCLC) treated non-invasively with stereotactic body radiotherapy (SBRT). Methods To assess the association between sarcopenia and clinical outcomes, we conducted a retrospective analysis of consecutive patients treated with SBRT from 2013 to 2019 . Overall survival (OS), local failure free survival (LFS), distant failure free survival (DFS), NTPA, body mass index (BMI), and Charlson comorbidity index (CCI) were included for analysis. NTPA was calculated by measuring the psoas volume at the L3 vertebra and normalizing for patient height and gender. Survival functions were evaluated using the Kaplan-Meier method. Log-rank test and Cox-proportional hazards were performed for categorical and continuous variables, respectively. Significance was set as p < 0.05. Results A total of 91 patients met the criteria. The median age was seven years and Karnofsky Performance Status score (KPS) was 80 (range: 60-100). Approximately 79% of patients had T1 tumors. Median radiation dose and number of fractions were 60 Gy (range: 45-60) and 5 fractions (range: 3-5). Median NTPA was 531.16 mm2/m2 (range: 90.4-1356.2). After normalization (sarcopenia

Background Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription. Methods and Materials We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BEDmin); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BEDmax); and (3) the average between near-minimum and near-maximum doses (yielding BEDave). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion. Results There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BEDave was the best predictor of risk of local recurrence, and a model based on BEDmin had substantially less evidential support. In univariable logistic regression, the model based on BEDave also performed best. Multivariable classification using fast and frugal trees revealed BEDmax to be the most important predictor, followed by BEDave. Conclusions BEDave was generally better correlated with tumor control probability than either BEDmax or BEDmin. Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation.

Importance: The COVID-19 pandemic is currently accelerating. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) may require treatment in locations where resources are limited and the prevalence of infection is high. Patients with LA-NSCLC frequently present with comorbidities that increase the risk for severe morbidity and mortality from COVID-19. These risks may be further increased by treatments for LA-NSCLC. Observation: We present expert thoracic oncology multidisciplinary (radiation oncology, medical oncology, surgical oncology) consensus of alternative strategies for the treatment of LA-NSCLC during a pandemic. The overarching goals of these approaches are to reduce the number of visits to a healthcare facility, reduce the risk of SARS-CoV-2 exposure, and attenuate the immunocompromising effects of lung cancer therapies. Patients with resectable disease can be treated with definitive non-operative management if surgical resources are limited or the risks of perioperative care are high. Non-operative options include chemotherapy, chemoimmunotherapy, and radiation therapy with sequential schedules. The order of treatments may be based on patient factors and clinical resources. Whenever radiation therapy is delivered without concurrent chemotherapy, hypofractionated schedules are appropriate. For patients who are confirmed to have COVID-19, usually cancer therapies may be withheld until symptoms have resolved with negative viral test results. Conclusions and Relevance: The risk of severe treatment-related morbidity and mortality is significantly elevated for patients undergoing treatment for LA-NSCLC during the COVID-19 pandemic. Adapting alternative treatment strategies as quickly as possible may save lives and should be implemented through communication with the multidisciplinary cancer team.

The coronavirus disease 2019 (COVID-19) pandemic is currently accelerating. Patients with locally advanced NSCLC (LA-NSCLC) may require treatment in locations where resources are limited, and the prevalence of infection is high. Patients with LA-NSCLC frequently present with comorbidities that increase the risk of severe morbidity and mortality from COVID-19. These risks may be further increased by treatments for LA-NSCLC. Although guiding data is scarce, we present an expert thoracic oncology multidisciplinary (radiation oncology, medical oncology, surgical oncology) consensus of alternative strategies for the treatment of LA-NSCLC during a pandemic. The overarching goals of these approaches are the following: (1) reduce the number of visits to a health care facility, (2) reduce the risk of exposure to severe acute respiratory syndrome-coronavirus-2, (3) attenuate the immunocompromising effects of lung cancer therapies, and (4) provide effective oncologic therapy. Patients with resectable disease can be treated with definitive nonoperative management if surgical resources are limited or the risks of perioperative care are high. Nonoperative options include chemotherapy, chemoimmunotherapy, and radiation therapy with sequential schedules that may or may not affect long-term outcomes in an era in which immunotherapy is available. The order of treatments may be on the basis of patient factors and clinical resources. Whenever radiation therapy is delivered without concurrent chemotherapy, hypofractionated schedules are appropriate. For patients who are confirmed to have COVID-19, usually, cancer therapies may be withheld until symptoms have resolved with negative viral test results. The risk of severe treatment-related morbidity and mortality is increased for patients undergoing treatment for LA-NSCLC during the COVID-19 pandemic. Adapting alternative treatment strategies as quickly as possible may save lives and should be implemented through communication with the multidisciplinary cancer team.

Background The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. Objective To examine these uncertainties. Methods NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method. Results A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test-Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. Conclusion STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.

PURPOSE To evaluate the clinical behavior of spheno-orbital meningiomas with regard to World Health Organization (WHO) tumor grade and Ki-67, a cellular marker of proliferation. METHODS A retrospective review over a 16-year period of the demographic, clinical, radiographic, and surgical data of all patients with spheno-orbital meningioma who underwent surgical resection. Tumor specimens were examined histologically using the current WHO 2016 classification and immunohistochemically using Ki-67/MIB-1 monoclonal antibody. RESULTS Thirty-eight patients met all inclusion criteria: 78.9% of tumors were WHO grade I with a mean Ki-67 of 3.76, and 93% of patients were clinically stable at last follow up; 10.5% of lesions were WHO grade II (atypical) with a mean Ki-67 of 14.93, and 10.5% of lesions were WHO grade III (anaplastic) with a mean Ki-67 of 58.3. All grade II and III meningiomas exhibited an aggressive clinical course. There were statistically significant correlations between disease clinical progression and WHO tumor grade (p < 0.001), between disease clinical progression and Ki-67 (p < 0.001), and between increasing Ki-67 index and higher WHO grade (p < 0.001). For WHO grade I lesions, a Ki-67 of ≥3.3 correlated with recurrence (p = 0.0256). Overall, disease-specific mortality occurred in 5 (13%) patients. CONCLUSIONS Ki-67 index is a valuable marker to use in conjunction with WHO grade to predict meningioma behavior, particularly in histologically borderline lesions, and possibly to identify a subset of WHO grade I tumors at risk of recurrence. This combination of methods can aid in tailoring treatment and surveillance strategies.

Background We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

INTRODUCTION: Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) along with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. Secondary analysis of EF14 trial demonstrated TTFields treatment may increase the rate of distant recurrence. We report our experience evaluating areas of progression in our pilot clinical trial of concurrent chemoradiation with TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from primary enhancing lesion. RESULTS: A total of 30 patients were enrolled on the trial. Twenty were male, and ten were female, with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 11.6 months (1.7-22.1 months). Twenty (66.7%) patients had an unmethylated MGMT promotor status and ten (33.3%) patients had a methylated promoter status. Twenty patients (66.7%) had progression, with median PFS of 9.1 months (range 1.6 to 12.9 months). Five patients (26%) of patient presented with distant recurrence, with median distance from primary lesion of 5.1 cm (2.26-9.12 cm). One infratentorial progression was noted. Another patient transferred care and location of progression is unknown. CONCLUSIONS: Concurrent chemoradiation with TTFields for patients with newly diagnosed glioblastoma may have increased incidence of distant recurrence. This finding is suggestive of improved local control of primary site. Further data are needed to validate this finding.

Purpose/Objective(s) Recent studies suggest improved local control (LC) of early-stage non-small cell lung cancer (NSCLC) treated with SBRT regimens with biologically equivalent dose (BED10) > 150 Gy. It is unclear if this association is histology dependent. Multiple groups have shown lower LC rates after SBRT for squamous cell carcinoma (SCC), compared to non-SCC NSCLC. We compared LC between BEDlow and BEDhigh SBRT schemes, stratified by histology. Materials/Methods As part of an IRB approved collaborative, we retrospectively analyzed 684 patients with cT1-2, cN0, cM0 NSCLC, treated with definitive SBRT to a minimum BED of 100 Gy at five international centers. Patients were grouped into SCC and non-SCC, then divided into BEDhigh (BED10 ≥150 Gy) or BEDlow (BED10 Results Of 684 eligible tumors, 457 were non-SCC and 227 SCC. Median follow-up was 30 months. Of non-SCC patients, 262 (57%) were BEDlow and 195 (43%) BEDhigh. Of SCC patients, 144 (63%) were BEDlow and 83 (37%) BEDhigh. BEDhigh SBRT included those treated with 54 Gy in 3 fractions (54/3). BEDlow included 60/5, 50/5, 48/4, or 60/8. Baseline characteristics, including T-stage and max tumor dimension, were similar between BED groups after matching. MVA including T-stage, tumor grade, and tumor location, showed BEDlow regimens were associated with higher rates of local failure for SCC (HR 9.8, 95% CI 1.9-25.1, P = 0.007), but not for non-SCC (HR 1.2, 95% CI 0.6-2.5, P = 0.6). Three-year LC rates for BEDlow and BEDhigh were 70% and 97%, respectively for SCC, and 91% and 92%, respectively, for non-SCC. Similarly, there were higher rates of failure with BEDlow PTVmean (3 yr LC 94 vs 69%, MVA HR 6.4, 95% CI 1.9-22.2, P = 0.003) and BEDlow GTVmean (3 yr LC 87 vs 68%, MVA HR 7.6, 95% CI 2.7-21.6, P = 0.001) in SCC patients. In non-SCC patients, LC was similar between BED groups for PTVmean (3 yr LC 92% vs 93%, MVA HR 1.1, 95% CI 0.5-2.8, P = 0.8) and GTVmean (3 yr LC 94 vs 90%, MVA HR 0.8, 95% CI 0.3-2.6, P = 0.8). There was a trend of worse survival in BEDlow SCC patients (MVA HR 1.3, 95% CI 0.9-1.9, P = 0.1), but survival was similar in non-SCC patients (MVA HR 1.02, 95% CI 0.8-1.3, P = 0.9). There were no differences in regional recurrence or distant metastases between BED groups in either histology. Conclusion This multi-institutional analysis shows improved LC in early-stage SCC NSCLC treated with SBRT regimens with BED10 > 150 Gy. No difference was observed in LC between BED groups for non-SCC patients. Our results suggest BEDhigh SBRT should be strongly considered for early-stage non-central SCC NSCLC.

Purpose/Objective(s) Radiation is an important treatment modality for patients with newly diagnosed gliomas. However, conventional radiation may cause microvascular changes resulting in loss of scalp thickness, elasticity and vascularization. This may increase the risk of wound complication and affect patients’ quality of life. Scalp-sparing VMAT can significantly reduce scalp radiation dose. We conducted a single-arm phase 2 trial evaluating scalp thickness, quality of life, and toxicities in patients treated on a scalp-sparing VMAT with concurrent chemotherapy. Materials/Methods This study is a single-arm phase 2 single-institution study. Adult patients (≥18 years old) with newly diagnosed grade II-IV gliomas, KPS ≥60, with an estimated survival ≥3 months, received surgical resection or biopsy, and require radiation treatment were eligible. Patients with any prior cranial radiation, intolerance to radiation, co-morbidities affecting wound-healing were excluded. Scalp-sparing intensity modulated radiation (20 cc of scalp overlying the bone plate received ≤50 Gy) were used. The primary endpoint is incidence of wound infection and/or wound dehiscence 90 days or later post-radiation treatment. Scalp thickness was measured prior to, 9 months and 18 months following treatment. Incidence of wound infection, adverse events and quality of life was recorded. Results Forty-six patients were enrolled. 41 patients completed evaluation at 30 days after first treatment, and 18 patients completed 9-month time point at the time of abstract submission. Median age at enrollment was 59.7 yo (22.2-82.6 yo). Twenty-seven patients had WHO grade IV, 12 patients with grade III, and 2 patients with grade II gliomas. Forty patients also received concurrent temozolomide. The median radiation dose is 60 Gy. Mean D20cc was 3001 cGy (1533-4408 cGy) and mean D30cc was 2378 cGy (594 – 3930 cGy). Scalp thickness decreased by an average of 10% (2-31%) and 19% (6-32%) at 9 and 18 months following CRT respectively. No patients had wound infections or dehiscence. This meets the preset benchmark of 5%. Twenty-one patients experienced grade 1 or 2 alopecia within 30 days of CRT completion. Eight patients experienced grade 1 dermatitis and one experienced grade 2 dermatitis all of which were during radiation treatment. The finds compared favorable to historical control. Conclusion Scalp-sparing VMAT is a feasible technique. The treatment is well tolerated with no significant scalp related complications. Further study is warranted to confirm the clinical benefits. Author Disclosure A. Ali: None. M.Z. Niazi: None. D.W. Andrews: None. J. Evans: None. K. Judy: None. C. Farrell: None. J. Glass: None. L. Kim: None. N. Martinez: None. I. Alnahhas: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. V. Bar-Ad: None. B.E. Leiby: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, BrainLab, Regeneron. Consultant; Varian, BrainLab, Zai lab.