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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/.

We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.Patients (23% of patients developed myelotoxicity (Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Background We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02–3.27) and being female (OR, 4.45; 95% CI, 2.45–8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43–1.89). Conclusions Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Background Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. Methods NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. Results A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. Conclusion The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.

PURPOSE NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

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.

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.

BACKGROUND: Even though TMZ is well tolerated by most GBM patients, some experience severe myelotoxicity, resulting in treatment delay or cessation. Our ultimate goal is to develop robust risk prediction models for toxicity, which incorporate both clinical and genetic variables. Predicting risk of toxicity would allow for treatment optimization: lower dosing for at-risk patients; full dose for low-risk patients. METHODS: Logistic regression with backward variable selection (p ≤ 0.05) was used to select the best fitting clinical model. A genome-wide analysis of genetic variation associated with myelotoxicity in glioblastoma patients from RTOG 0825 was then conducted. The top hits were then incorporated into the risk modeling strategy to increase our ability to predict toxicity. Tagging variants were selected and examined individually and jointly (by summing the number of adverse genotypes). RESULTS: Clinical and genotype data from 367 cases were included. The final clinical model included the following variables: treatment arm, gender, Karnofsky performance status (KPS), anticonvulsant use, and body surface area (BSA). The area under the curve (AUC) for the clinical model was 0.69. The genome scan revealed ten polymorphisms in MGMT that were significantly associated with myelotoxicity (p < 10−8). The most significant variant in the genome scan resulted in the best model (AUC = 0.80) for an individual SNP. Individuals with the risk allele in this SNP exhibited a 5.3-fold increase in risk of myelotoxicity compared to those with the non-risk allele (p < 0.0001, 95%CI: 3.2-8.7) after adjusting for the clinical variables and independent of survival. The final model with genetic dose performed equally as well as the model with the single MGMT SNP. CONCLUSIONS: TMZ myelotoxicity is a significant clinical issue. The addition of genetic variants in MGMT greatly improved the performance of our clinical risk model. Future work will continue to improve prediction by examining other genetic variants and potential interactions between variants.

Stereotactic body radiotherapy (SBRT) has emerged as an important treatment option for spinal metastases from renal cell carcinoma (RCC) as a means to overcome RCC's inherent radioresistance. The authors reviewed the outcomes of SBRT for the treatment of RCC metastases to the spine at their institution, and they identified factors associated with treatment failure.Fifty-seven patients (88 treatment sites) with RCC metastases to the spine received single-fraction SBRT. Pain relief was based on the Brief Pain Inventory and was adjusted for narcotic use according to the Radiation Therapy Oncology Group protocol 0631. Toxicity was scored according to Common Toxicity Criteria for Adverse Events version 4.0. Radiographic failure was defined as infield or adjacent (within 1 vertebral body [VB]) failure on follow-up MRI. Multivariate analyses were performed to correlate outcomes with the following variables: epidural, paraspinal, single-level, or multilevel disease (2-5 sites); neural foramen involvement; and VB fracture prior to SBRT. Kaplan-Meier analysis and Cox proportional hazards modeling were used for statistical analysis.The median follow-up and survival periods were 5.4 months (range 0.3-38 months) and 8.3 months (range 1.5-38 months), respectively. The median time to radiographic failure and unadjusted pain progression were 26.5 and 26.0 months, respectively. The median time to pain relief (from date of simulation) and duration of pain relief (from date of treatment) were 0.9 months (range 0.1-4.4 months) and 5.4 months (range 0.1-37.4 months), respectively. Multivariate analyses demonstrated that multilevel disease (hazard ratio [HR] 3.5, p = 0.02) and neural foramen involvement (HR 3.4, p = 0.02) were correlated with radiographic failure; multilevel disease (HR 2.3, p = 0.056) and VB fracture (HR 2.4, p = 0.046) were correlated with unadjusted pain progression. One patient experienced Grade 3 nausea and vomiting; no other Grade 3 or 4 toxicities were observed. Twelve treatment sites (14%) were complicated by subsequent vertebral fractures.Stereotactic body radiotherapy for RCC metastases to the spine offers fast and durable pain relief with minimal toxicity. Stereotactic body radiotherapy seems optimal for patients who have solitary or few spinal metastases. Patients with neural foramen involvement are at an increased risk for failure.

BACKGROUND: Tumor response and treatment-related toxicities vary greatly among patients despite careful selection criteria and accurate drug dosing. This projects was to evaluate risk and validate prediction models for vascular toxicity in patients with newly diagnosed GBM treated with bevacizumab. METHODS: We tabulated the incidence of cardiac and vascular toxicity in RTOG0525 (standard vs. dose-dense temozolomide) and RTOG0825 (bevacizumab (BEV) vs placebo). Based on the data collected from RTOG0825 BEV containing arm, a risk prediction model for hypertension (Grade 2-4) and thrombosis (Grade 3-4) was built based on known risk factors. Candidate risk factors were screened using univariable logistic regression (significance 0.15), then included in a multivariable model (significance 0.05) to determine the final risk model. RESULTS: In RTOG0825, overall incidence of hypertension was 11% (67/591) and thrombosis (73/591) 12%. Hypertension was higher with BEV (15 vs 8%) and no difference found for thrombosis (12 vs 13%). Men experienced more toxicity than women (12 vs 10% hypertension; 14 vs 9% thrombosis) but this was not significant at 0.05. None of the known risk factors for hypertension and thrombosis with BEV were significant in the final risk prediction model. For comparison, in RTOG0525, the incidence of cardiac toxicity was 4% (27/720) and thrombosis was 6%. CONCLUSIONS: Patients enrolled on these clinical trials had a lower overall incidence of both adverse events than would be expected in this demographic (middle aged or older with underlying glioblastoma where the incidence of hypertension is 30% and thromboembolism of 15%). Previously described risk factors were not confirmed, but may reflect selection by eligibility criteria of a healthier patient cohort compared with a population-based cohort. While clinical risk factors were unrevealing, planned genomic phenotyping focusing on polymorphisms may elucidate informative risk profiles. Supported by NCI grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA114734, NIH grant 1R01NR013707, and Genentech.

INTRODUCTION: We previously reported the unexpected finding that survival was significantly improved in patients with newly-diagnosed GBM when radiation was initiated later (>4 weeks post-op) compared to earlier (≤2 weeks post-op). That analysis included 2855 patients from 16 RTOG trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1127 patients from two studies involving newly-diagnosed GBM, treated with RT + 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 on both arms of RTOG 0525 and the placebo arm of RTOG 0825 were investigated. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT in the RT + TMZ era. Overall survival was investigated using Cox proportional hazard model. Progression from diagnosis to 30 days after RT completion was analyzed using Chi-square test. RESULTS: 94.9% of the patients started RT 2-5 weeks post-op. Given the small number of patients who started RT early, comparisons were made between >4 and ≤4 weeks delay of radiation. There was no statistically significant difference for overall survival (p-value = 0.29; HR = 0.93; 95% CI: 0.80-1.07) after adjusting for RPA and MGMT methylation status. Similarly, the rate of early progression did not differ significantly (p-value = 0.59). CONCLUSIONS: We did not see a significant prognostic influence of delaying radiation within the range of 2-5 weeks post-op when given concurrently with TMZ for newly-diagnosed GBM. TMZ may "level the playing field" for patients treated with chemoradiation and offset the effect of RT delay that was seen when RT was given alone; however, the effects of early initiation of radiation tested previously could not be replicated. Supported by National Cancer Institute grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422, Merck & Co. and Genentech.