Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033

Background: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning. Methods: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time. Results: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes. Conclusion: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy. Keywords: chemotherapy; low-grade glioma; memory functioning; radiotherapy

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

BackgroundOfranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.MethodsThis pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).ResultsEnrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.ConclusionsIn this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.Clinical trials registrationNCT02511405

The Clinical Significance of Ependymal Enhancement at Presentation in Patients with Malignant Glioma

Introduction. The current study evaluated the rate of ependymal enhancement and whether its presence influences survival of patients with malignant glioma (GBM). Methods. A retrospective review of all patients who were treated in our institution from 2005 to 2011 was conducted. Data extracted from the medical records included age, date of diagnosis, co-morbidities, treatment regimen, and time of death. Magnetic resonance images (MRI) were evaluated for the presence of ependymal enhancement and its extent, and the correlation to survival was investigated. Results. Between 2005 and 2011, 230 patients were treated for GBM. Eighty-nine patients were excluded from the study due to insufficient data, leaving 141 patients for analysis. Median age at diagnosis was 60 years. Sixty-seven (40.6%) patients had evidence of ependymal enhancement on MRI (group A), and 70 (42.4%) patients did not have evidence of enhancement. The assessment of ependymal enhancement was inconclusive due to mass effect and ventricular compression that precluded accurate assessment for 28 (17%) patients (group C). Median survival was 14 months for group A (range, 12–16 months), 15.9 months for group B (range, 14.28–17.65 months), and 11.7 months for group C (range, 6.47–16.92 months) (P>0.05). A multivariate analysis to predict survival indicated that male gender (P=0.039), hypertension (P=0.012), and biopsy only compared to complete gross tumor resection (P=0.001) were significant for poor survival. Conclusions. Pretreatment ependymal enhancement on MRI was not found to be associated with poorer survival. These results might be due to better treatments options compared to prior reports

Impact of Radiation Target Volume on Health-Related Quality of Life in Patients With Low-Grade Glioma in the 2-Year Period Post Treatment: A Secondary Analysis of the EORTC 22033-26033

Purpose: It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL. Methods and Materials: We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time. Results: We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue. Conclusions: The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated

Impact of Radiation Target Volume on Health-Related Quality of Life in Patients With Low-Grade Glioma in the 2-Year Period Post Treatment: A Secondary Analysis of the EORTC 22033-26033

Purpose: It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL. Methods and Materials: We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time. Results: We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue. Conclusions: The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated

Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial

PURPOSE: Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. PATIENTS AND METHODS: This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. RESULTS: A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. CONCLUSION: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated