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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 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: 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.