Temozolomide-based Chemoradiotherapy Research Articles

NIMG-51. PROSPECTIVE CASE CONTROL STUDY OF HYPOXIA FMISO PET/MRI AS A DIAGNOSTIC FEATURE OF GLIOBLASTOMA IMMUNOTHERAPY FAILURE

Abstract BACKGROUND Hypoxia is a prognostic biological feature of glioblastoma. 18F-fluoromisonidazole (FMISO) PET quantifies tumor hypoxia. Efficacy of checkpoint immunotherapy is being investigated, but specific response assessment criteria remain unknown. We hypothesized that tumor hypoxia is a defining feature of immunotherapy failure in patients with glioblastoma. METHODS A prospective case control study was undertaken in patients with newly diagnosed IDH wildtype glioblastoma (NCT03649880). Cases were concurrently enrolled in a phase II study (NCT03347617) of pembrolizumab immunotherapy (200 mg IV every 3 weeks) combined with Stupp protocol temozolomide-based chemoradiotherapy following maximal safe resection. Controls did not receive pembrolizumab. FMISO PET/MRI (3.7 MBq/kg, 90 min uptake) was performed at time of mRANO presumed progression. Hypoxic volume (HV) was defined by pixels with FMISO uptake ≥1.2x that of mean cerebellar uptake. MRI-Gd enhancing volume was segmented using a semi-automated approach. Hypoxic fraction (HF) was defined as the HV-to-MRI enhancing volume ratio. Disease progression or pseudoprogression (Psp) was confirmed through surgery or follow-up MRI. T-test and receiver operator characteristic (ROC) analysis assessed differences and diagnostic performance. RESULTS 18 patients (14 cases [11 progression and 3 Psp] and 4 controls [3 progression and 1 Psp]) provided evaluable disease. For all patients, HF was significantly elevated with progression (1.44 ± 0.8; N=14) compared to Psp (0.31 ± 0.3; N= 4; P=0.01). HV was not different (P=0.10). No difference in HV or HF was observed between Cases and Controls (P> 0.42). Use of HF yielded an AUROC of 0.96 with an optimal cut off of 0.74, to differentiate progression from Psp. CONCLUSION At mRANO presumed progression HF with FMISO PET/MRI accurately distinguishes tumor progression from neuroinflammatory Psp, irrespective of prior pembrolizumab immunotherapy. The incorporation of FMISO PET/MRI in larger prospective therapeutic clinical trials in patients with glioblastoma is underway and likely to improve response assessment criteria.

Prognostic survival biomarkers of tumor-fused dendritic cell vaccine therapy in patients with newly diagnosed glioblastoma

Dendritic cell (DC)-based immunotherapy has been applied to glioblastoma (GBM); however, biomarkers informing response remain poorly understood. We conducted a phase I/IIa clinical trial investigating tumor-fused DC (TFDC) immunotherapy following temozolomide-based chemoradiotherapy in patients with newly diagnosed GBM and determined prognostic factors in patients receiving TFDC immunotherapy. Twenty-eight adult patients with GBM isocitrate dehydrogenase (IDH) wild-type (IDH-WT) were enrolled; 127 TFDC vaccine injections (4.5 ± 2.6 times/patient) were administered. Patients with GBM IDH-WT had a respectable 5-year survival rate (24%), verifying the clinical activity of TFDC immunotherapy, particularly against O6-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM (5-year survival rate: 33%). To identify novel factors influencing overall survival (OS) in GBM IDH-WT treated with TFDC immunotherapy, clinical parameters were assessed and comprehensive molecular profiling involving transcriptome and exome analyses was performed. MGMT promoter methylation status, extent of tumor resection, and vaccine parameters (administration frequency, DC and tumor cell numbers, and fusion ratio) were not associated with survival following TFDC immunotherapy. Old age and pre- and post-operative Karnofsky performance status were significantly correlated with OS. Low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were correlated with better prognosis. We validated the activity of TFDC immunotherapy against GBM IDH-WT, including chemoresistant, MGMT promoter unmethylated cases. The identification of molecular biomarkers predictive of TFDC immunotherapy efficacy in GBM IDH-WT will facilitate the design of and patient stratification in a phase-3 trial to maximize treatment benefits.

Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors

BackgroundRadiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution.MethodsThe treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed.ResultsPlan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05).ConclusionIn our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.

P09.03.A Associations of levetiracetam use with the safety and tolerability of chemoradiotherapy for patients with newly diagnosed glioblastoma

Abstract Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Patients and Methods In a retrospective analysis of individual patient data using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, p&amp;lt;0.001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR=0.80, p=0.017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusion Any association of psychiatric adverse events with LEV did not persist beyond the concomitant treatment phase. Antiemetic properties of LEV may be beneficial during the maintenance temozolomide.

Associations of levetiracetam use with the safety and tolerability profile of chemoradiotherapy for patients with newly diagnosed glioblastoma.

BackgroundLevetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap.MethodsUsing a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment.ResultsOf 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, P < .001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR = 0.80, P = .017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events.ConclusionsLEV is not associated with reduced tolerability of chemoradiotherapy in patients with glioblastoma regarding hematologic toxicity and fatigue. Antiemetic properties of LEV may be beneficial during maintenance temozolomide.

The Efficacy of Maximal Tumor Resection Combined With Whole Ventricle Radiotherapy in Patients With Glioblastoma Involving the Ventricle

Patients with glioblastoma (GBM) that involve the ventricle are at higher risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the role of whole ventricular radiotherapy (WVRT) during postoperative temozolomide-based chemoradiotherapy.A retrospective review of 382 patients with GBM who received surgical resection followed by temozolomide-based chemoradiotherapy between 2005 to 2019 at a single institution was conducted. Propensity score matching was performed to compensate the difference in characteristics between patients that did (WVRT(+); n = 59) or did not (WVRT(-); n = 323) receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.All WVRT(+) patients had tumor ventricle involvement and ventricle opening during surgery. In the propensity matched cohort, WVRT(+) group exhibited a significantly lower 2-year intraventricular failure rate compared to the WVRT(-) group (2.1% vs. 11.8%; P = 0.045), but no difference in other treatment outcomes. Recursive partitioning analysis stratified patients at higher risk of intraventricular failure (tumor ventricle involvement, MGMT unmethylation, and ventricle opening) with a 2-year rate of 14.2%. WVRT reduced intraventricular failure rates only in high-risk patients (0% vs. 14.2%; P = 0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P = 0.036). WVRT did not cause a significant decline in performance status but caused a decrease in post-treatment absolute lymphocyte count, although it was recovered to a similar level with that of the WVRT(-) group.WVRT reduced intraventricular failure rates in patients with tumor ventricle involvement and ventricle opening during surgery. Our results merit further prospective evaluation of WVRT in GBM.K. Kim: None. J. Yoo: None. S. Kang: None. J. Chang: None. H. Yoon: None. C. Suh: None.

Efficacy of Whole-Ventricular Radiotherapy in Patients Undergoing Maximal Tumor Resection for Glioblastomas Involving the Ventricle.

Background and PurposePatients with glioblastoma (GBM) involving the ventricles are at high risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the effectiveness of whole-ventricular radiotherapy (WVRT) in reducing intraventricular seeding in patients with GBM and identified patients who could benefit from this approach.Methods and MaterialsWe retrospectively reviewed the data of 382 patients with GBM who underwent surgical resection and temozolomide-based chemoradiotherapy. Propensity score matching was performed to compensate for imbalances in characteristics between patients who did [WVRT (+); n=59] and did not [WVRT (–); n=323] receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.ResultsAll patients in the WVRT (+) group had tumor ventricular involvement and ventricle opening during surgery. In the matched cohort, the WVRT (+) group exhibited a significantly lower 2-year intraventricular failure rate than the WVRT (–) group (2.1% vs. 11.8%; P=0.045), with no difference in other outcomes. Recursive partitioning analysis stratified the patients in the WVRT (–) group at higher intraventricular failure risk (2-year survival, 14.2%) due to tumor ventricular involvement, MGMT unmethylation, and ventricle opening. WVRT reduced the intraventricular failure rate only in high-risk patients (0% vs. 14.2%; P=0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P=0.036).ConclusionsWVRT reduced the intraventricular failure rate in patients with tumor ventricular involvement and ventricle opening during surgery. The MGMT-methylation status may further stratify patients who could benefit from WVRT. Further prospective evaluation of WVRT in GBM is warranted.

Sex-based survival differences in IDH-wildtype glioblastoma: Results from a retrospective cohort study

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.

Survival impact of incidental subventricular zone irradiation in IDH-wildtype glioblastoma

Background and purpose The subventricular zone (SVZ) is an important niche for neural stem cells but probably also for brain tumor propagating cells, including the glioblastoma stem cell. The SVZ may become a target for radiation therapy in glioblastoma patients. However, reports studying the effect of irradiation of the SVZ on glioblastoma patient survival show conflicting results. We studied the correlation between incidental SVZ radiation dose and survival in a cohort of isocitrate dehydrogenase-wildtype (IDHwt) glioblastoma patients with inclusion of important survival prognosticators. Patients and methods In this retrospective analysis, only adult patients with supratentorial IDHwt glioblastoma were included who were treated with temozolomide-based chemoradiotherapy after surgery. The SVZ was contoured on the radiotherapy planning imaging. Cox proportional regression overall survival (OS) analysis was used to study the correlation between SVZ dose and survival. Age, Karnofsky Performance Score, extent of resection and O6-methylguanine-methyl-DNA-transferase gene promoter (MGMTp) methylation were used as covariates in multivariate analysis. Results In total, 137 patients were included. Median OS was 13.3 months. The MGMTp methylation was present in 40% of cases. Ipsilateral SVZ (iSVZ) mean dose was 44.4 Gy and 27.2 Gy for the contralateral SVZ (cSVZ). Univariate survival analysis showed an inverse relationship between cSVZ mean dose and OS (HR 1.029 (1.003–1.057); p= .032). However, there was no correlation between cSVZ mean dose and OS in multivariate analysis. iSVZ dose did not correlate with survival. Conclusion In this cohort of 137 IDHwt glioblastoma patients, iSVZ did not correlate with OS. Higher cSVZ dose was inversely correlated with OS in univariate survival analysis but lost its significance in multivariate analysis, including MGMTp-methylation. Hence, the correlation between SVZ radiation and glioblastoma patient survival remains unclear. Carefully designed prospective studies are needed to provide unequivocal results on this controversial topic.

Partial resection offers an overall survival benefit over biopsy in MGMT-unmethylated IDH-wildtype glioblastoma patients

BackgroundIsocitrate dehydrogenase (IDH)-wildtype glioblastoma patients with O6-methylguanine-DNA-methyltransferase (MGMT)-unmethylated tumors have the worst outcome of all glioblastoma patients. The overall survival (OS) benefit of partial resection of glioblastoma compared to biopsy only remains controversial specifically in relation to molecular factors. In this report, we analyzed the effect of incomplete resection on OS compared to biopsy only in a cohort of IDH-wildtype glioblastoma patients who were uniformly treated with temozolomide-based chemoradiotherapy (TMZ-CR) after surgery.Material & MethodsA retrospective study was conducted including only glioblastoma patients who were treated with TMZ-CR after surgery from two centers. Surgical groups were defined as biopsy only, partial resection (PR) or gross total resection depending on the presence of contrast-enhancing tumor on postoperative imaging. IDH-mutation was determined using next generation sequencing technique and MGMT-methylation was analyzed with semi-quantitative methylation-specific polymerase chain reaction. Next to descriptive statistics, univariate and multivariate survival analyses were performed using Kaplan-Meier estimates and Cox regression models.ResultsIn total, 159 patients were included. 37 patients underwent biopsy only and 73 partial resections. 99 patients (62.3%) harbored unmethylated tumors. Median OS for the whole patient group was 13.4 months. In the subgroup of patients with unmethylated tumors, PR yielded a median OS of 12.2 months vs 7.6 months for biopsy patients (P = 0.003). PR proved an independent beneficial prognostic factor in multivariate Cox regression model, together with age, Karnofsky Performance Score and MGMT-methylation.ConclusionIn IDH-wildtype glioblastoma patients with MGMT-unmethylated tumors, treated with chemoradiotherapy after surgery, PR yields a significant OS benefit compared to biopsy.

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

Background Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. Patients and methods We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. Results A total of 214 patients were included in the study of whom 68% belonged to the SVZpos group. Median tumor volume was significantly larger in the SVZpos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZpos group (61.4% vs 44.9%; p = .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZpos patient group but 16.9 months and 10.3 months for the SVZneg group (log-rank p = .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. Conclusions This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZpos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZneg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZpos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

Steroids use and survival in patients with glioblastoma multiforme: a pooled analysis.

Steroids are commonly used for managing brain edema in patients with glioblastoma multiforme (GBM), treated with surgery and concomitant temozolomide-based chemoradiotherapy (CTRT). The adverse effects of glucocorticoids include lymphopenia, hyperglycemia, and risk of infection. We report the results of a meta-analysis evaluating the effects of steroids on outcome when associated with the treatment of GBM. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with GBM and treated or not treated with steroids. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with the worst outcome in steroid users compared to non-users. Twenty-two publications were retrieved from studies selected for a total of 8,752 patients. In the primary analysis (n = 22 studies reporting data), OS was reduced in GBM patients taking steroids during treatment (HR = 1.54, 95% CI 1.37-1.75; p < 0.01). Similarly, PFS was inferior in steroid users in n = 9 studies with data available (HR = 1.28, 95% CI 1.1-1.49; p < 0.01). In patients with GBM and treated with RT and/or CT, association with steroids significantly reduces survival and PFS. Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals and prevention of steroid-associated complications are essential aims of treatment of this disease.

Validation and optimization of aweb-based nomogram for predicting survival of patients with newly diagnosed glioblastoma.

To optimize and validate acurrent (NRG [anewly constituted National Clinical Trials Network group through National Surgical Adjuvant Breast and Bowel Project [NSABP], the Radiation Therapy Oncology Group [RTOG] and the Gynecologic Oncology Group (GOG)]) nomogram for glioblastoma patients as part of continuous validation. We identified patients newly diagnosed with glioblastoma who were treated with temozolomide-based chemoradiotherapy between 2006 and 2016 at three large-volume hospitals. The extent of resection was determined via postoperative MRI. The discrimination and calibration abilities of the prediction algorithm were assessed; if additional factors were identified as independent prognostic factors, updated models were developed using the data from two hospitals and were externally validated using the third hospital. Models were internally validated using cross-validation and bootstrapping. A total of 837 patients met the eligibility criteria. The median overall survival (OS) was 20.0 (95% CI 18.5-21.5) months. The original nomogram was able to estimate the 6‑, 12-, and 24-month OS probabilities, but it slightly underestimated the OS values. In multivariable Cox regression analysis, MRI-defined total resection had agreater impact on OS than that shown by the original nomogram, and two additional factors-IDH1mutation and tumor contacting subventricular zone-were newly identified as independent prognostic values. An updated nomogram incorporating these new variables outperformed the original nomogram (C-index at 6, 12, 24, and 36months: 0.728, 0.688, 0.688, and 0.685, respectively) and was well calibrated. External validation using an independent cohort showed C‑indices of 0.787, 0.751, 0.719, and 0.702 at 6, 12, 24, and 36months, respectively, and was well calibrated. An updated and validated nomogram incorporating the contemporary parameters can estimate individual survival outcomes in patients with glioblastoma with better accuracy.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial

BackgroundThe addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT → TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methodsARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. ResultsMedian PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%–100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). ConclusionEfficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration numberNCT01443676.

Neutrophilia as a biomarker for overall survival in newly diagnosed high-grade glioma patients undergoing chemoradiation

ObjectiveTo study the prognostic value of neutrophil disorders in a retrospective cohort of high-grade glioma patients receiving definitive concurrent temozolomide and radiation. Materials and methodsClinical records of consecutive patients treated in our Institution between January 2005 and December 2010 with concurrent temozolomide (75 mg/m2 daily) and radiation were collected. The prognostic value of pretreatment neutrophilia on survival, defined as a neutrophil count exceeding 7 G/L, was examined. ResultsWe identified 164 patients, all treated with concurrent temozolomide-based chemoradiotherapy. Initial surgery was achieved in most (75%), with resection > 90% in 55 patients (34%). Total 151 patients (92%) had glioblastoma, and 13 patients (8%) had WHO grade III glioma. Eighty-two patients (50%) displayed pretreatment neutrophilia. Neutrophilia was not associated with concurrent or adjuvant temodal discontinuation (p > 0.3). The 2-year actuarial overall survival was 45%. Steroid consumption, i.e. 60 mg or more of daily prednisolone, increased pretreatment neutrophil count (p = 0.005). In univariate analysis, neutrophilia was associated with worse overall survival (p = 0.019), as well as age ≥ 65 years (p = 0.009), surgical resection < 90% (p = 0.003) and prednisolone consumption ≥ 60 mg/day (p = 0.016). In multivariate analysis, neutrophilia (p = 0.013), age ≥ 65 (p = 0.001), and surgical tumor resection < 90% (p = 0.010) independently decreased overall survival, while, steroid consumption was not (p = 0.088). ConclusionIn high-grade gliomas treated with concurrent temozolomide and radiation, pretreatment neutrophilia may be a significant prognosis factor for overall survival. In addition with previously available markers, this independent cost-effective biomarker could help identifying patients with worsened prognosis.

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan–Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68–1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival.

Management of Elderly Patients with Glioblastoma.

Glioblastoma represents one of the major challenges in neurooncology and approximately half of the patients are 60years or older. We summarize the particular situation of elderly glioblastoma patients with a focus on therapeutic considerations. Favorable molecular markers such as mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes are virtually absent in glioblastomas in elderly patients. Treatment options are similar to the situation in young patients and comprise surgical resection, radiation therapy, and alkylating chemotherapy. The performance status as well as comorbidities may have a stronger impact on the individual treatment decision than in young patients. The MGMT promoter methylation status allows for a stratification of treatment beyond the surgical intervention. In patients with MGMT promoter methylated tumors, monotherapy with temozolomide is superior to radiotherapy alone. Similarly, the benefit conferred by combined temozolomide-based chemoradiotherapy compared to radiotherapy alone is largely restricted to patients with MGMT promoter-methylated tumors. At recurrence, no standard treatment has been established. The prognosis for elderly patients with glioblastoma remains poor. The MGMT promoter methylation status helps guiding treatment decisions and withholding inactive, but potentially harmful treatments.

Impact of Including Peritumoral Edema in Radiotherapy Target Volume on Patterns of Failure in Glioblastoma following Temozolomide-based Chemoradiotherapy

We assessed the impact of including peritumoral edema in radiotherapy volumes on recurrence patterns among glioblastoma multiforme (GBM) patients treated with standard chemoradiotherapy (CRT). We analyzed 167 patients with histologically confirmed GBM who received temozolomide (TMZ)-based CRT between May 2006 and November 2012. The study cohort was divided into edema (+) (n = 130) and edema (−) (n = 37) groups, according to whether the entire peritumoral edema was included. At a median follow-up of 20 months (range, 2–99 months), 118 patients (71%) experienced progression/recurrence (infield: 69%; marginal: 26%; outfield: 16%; CSF seeding: 12%). The median overall survival and progression-free survival were 20 months and 15 months, respectively. The marginal failure rate was significantly greater in the edema (−) group (37% vs. 22%, p = 0.050). Among 33 patients who had a favorable prognosis (total resection and MGMT-methylation), the difference in the marginal failure rates was increased (40% vs. 14%, p = 0.138). Meanwhile, treatment of edema did not significantly increase the incidence of pseudoprogression/radiation necrosis (edema (−) 49% vs. (+) 37%, p = 0.253). Inclusion of peritumoral edema in the radiotherapy volume can reduce marginal failures following TMZ-based CRT without increasing pseudoprogression/radiation necrosis.

IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy

PurposeThis study aimed to investigate the potential association between IDH mutation and O6–methyl-guanine methyl transferase (MGMT) gene promoter methylation and pseudoprogression disease (psPD) in glioblastoma multiforme (GBM) patients after concurrent temozolomide (TMZ)-based chemoradiotherapy. MethodsA total of 157 GBM patients who received concurrent TMZ-based chemoradiotherapy were included in this retrospective study. The association between psPD and a number of demographic and genetic factors, including IDH mutation and MGMT promoter methylation, were analyzed based on logistic regression, Cox regression, and multivariate analysis. ResultsOf the 157 GBM patients, 145 (92.36%) patients, including 38 patients with psPD, 38 patients with early progression (ePD), and 69 patients with non-progression (non-PD), were followed up for six to 56 months. We identified a higher rate of MGMT promoter methylation and IDH1 mutation in psPD patients compared with ePD patients (P=0.002). In addition, MGMT promoter methylation and IDH1 mutation predicted a high probability of psPD development in GBM patients (P=0.001 and P<0.001, respectively). MGMT promoter methylation, IDH1 mutation, Karnofsky performance score (KPS) ≥70, and psPD were associated with a significantly longer overall survival of GBM patients (P=0.001, 0.001, 0.002, and P<0.001, respectively). Both of MGMT promoter methylation and IDH mutation had a cumulative effect on the OS of GBM patients. GBM patients with psPD (39.2±2.1months, P<0.001) had a longer median survival (MS) than GBM patients with ePD (11.9±1.1months) or with non-PD (24.4±2.4months). ConclusionMGMT promoter methylation and IDH1 mutation were associated with PsPD and predicted a longer median survival in GBM patients after TMZ-based chemoradiotherapy. Genetic analyses of the MGMT promoter and IDH1 may allow us to effectively treat GBM patients.

Comparison of long-term survival between temozolomide-based chemoradiotherapy and radiotherapy alone for patients with low-grade gliomas after surgical resection.

PurposeThis study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection.Patients and methodsIn this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50–100 mg oral TMZ every day until the radiotherapy regimen was completed.ResultsThe median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and <45 years) and resection margin (complete resection or not) were significantly associated with OS (P=0.03 and P=0.004, respectively).ConclusionAlthough no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group. With better tolerability, concurrent TMZ chemoradiotherapy may be beneficial for postoperative patients with LGGs. Age distribution and surgical margin are likely potential indicators of disease prognosis. The possible differences in long-term survival between the two groups and the links between prognostic factors and long-term survival may be worthy of further investigation.