Parenteral high­dose ascorbate - A possible approach for the treatment of glioblastoma (Review).

For glioblastoma, the treatment with standard of care therapy comprising resection, radiation, and temozolomide results in overall survival of approximately 14-18 months after initial diagnosis. Even though several new therapy approaches are under investigation, it is difficult to achieve life prolongation and/or improvement of patient's quality of life. The aggressiveness and progression of glioblastoma is initially orchestrated by the biological complexity of its genetic phenotype and ability to respond to cancer therapy via changing its molecular patterns, thereby developing resistance. Recent clinical studies of pharmacological ascorbate have demonstrated its safety and potential efficacy in different cancer entities regarding patient's quality of life and prolongation of survival. In this review article, the actual glioblastoma treatment possibilities are summarized, the evidence for pharmacological ascorbate in glioblastoma treatment is examined and questions are posed to identify current gaps of knowledge regarding accessibility of ascorbate to the tumor area. Experiments with glioblastoma cell lines and tumor xenografts have demonstrated that high­dose ascorbate induces cytotoxicity and oxidative stress largely selectively in malignant cells compared to normal cells suggesting ascorbate as a potential therapeutic agent. Further investigations in larger cohorts and randomized placebo­controlled trials should be performed to confirm these findings as well as to improve delivery strategies to the brain, through the inherent barriers and ultimately to the malignant cells.

Maximal surgical resection and adjuvant surgical technique to prolong the survival of adult patients with thalamic glioblastoma.

The importance of maximal resection in the treatment of glioblastoma (GBM) has been reported in many studies, but maximal resection of thalamic GBM is rarely attempted due to high rate of morbidity and mortality. The purpose of this study was to investigate the role of surgical resection in adult thalamic glioblastoma (GBM) treatment and to identify the surgical technique of maximal safety resection. In case of suspected thalamic GBM, surgical resection is the treatment of choice in our hospital. Biopsy was considered when there was ventricle wall enhancement or multiple enhancement lesion in a distant location. Navigation magnetic resonance imaging, diffuse tensor tractography imaging, tailed bullets, and intraoperative computed tomography and neurophysiologic monitoring (transcranial motor evoked potential and direct subcortical stimulation) were used in all surgical resection cases. The surgical approach was selected on the basis of the location of the tumor epicenter and the adjacent corticospinal tract. Among the 42 patients, 19 and 23 patients underwent surgical resection and biopsy, respectively, according to treatment strategy criteria. As a result, the surgical resection group exhibited a good response with overall survival (OS) (median: 676 days, p < 0.001) and progression-free survival (PFS) (median: 328 days, p < 0.001) compared with each biopsy groups (doctor selecting biopsy group, median OS: 240 days and median PFS: 134 days; patient selecting biopsy group, median OS: 212 days and median PFS: 118 days). The surgical resection groups displayed a better prognosis compared to that of the biopsy groups for both the O6-methylguanine-DNA methyltransferase unmethylated (log-rank p = 0.0035) or methylated groups (log-rank p = 0.021). Surgical resection was significantly associated with better prognosis (hazard ratio: 0.214, p = 0.006). In case of thalamic GBM without ventricle wall-enhancing lesion or multiple lesions, maximal surgical resection above 80% showed good clinical outcomes with prolonged the overall survival compared to biopsy. It is helpful to use adjuvant surgical techniques of checking intraoperative changes and select the appropriate surgical approach for reducing the surgical morbidity.

Anti-PD-1 Immunotherapy in Preclinical GL261 Glioblastoma: Influence of Therapeutic Parameters and Non-Invasive Response Biomarker Assessment with MRSI-Based Approaches.

Glioblastomas (GBs) are malignant brain tumours with poor prognosis even after aggressive therapy. Programmed cell death-1 (PD-1) immune checkpoint blockade is a promising strategy in many types of cancer, but its therapeutic effects in GB remain low and associated with immune infiltration. Previous work suggests that oscillations of magnetic resonance spectroscopic imaging (MRSI)-based response pattern with chemotherapy could act as a biomarker of efficient immune system attack onto GBs. The presence of such oscillations with other monotherapies such as anti-PD-1 would reinforce its monitoring potential. Here, we confirm that the oscillatory behaviour of the response biomarker is also detected in mice treated with anti PD-1 immunotherapy both in combination with temozolomide and as monotherapy. This indicates that the spectral pattern changes observed during therapy response are shared by different therapeutic strategies, provided the host immune system is elicited and able to productively attack tumour cells. Moreover, the participation of the immune system in response is also supported by the rate of cured animals observed with different therapeutic strategies (in the range of 50-100% depending on the treatment), which also held long-term immune memory against tumour cells re-challenge. Taken together, our findings open the way for a translational use of the MRSI-based biomarker in patient-tailored GB therapy, including immunotherapy, for which reliable non-invasive biomarkers are still missing.

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme.

BACKGROUNDThe recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.METHODSTwenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro-expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution.RESULTSNo participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMV-specific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7-65 vs. median 14 months, range 5-19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival.CONCLUSIONData presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.TRIAL REGISTRATIONanzctr.org.au: ACTRN12615000656538.FUNDINGPhilanthropic funding and the National Health and Medical Research Council (Australia).

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

The role of neutrophil-to-lymphocyte ratio in predicting overall survival in patients undergoing laser interstitial thermal therapy for glioblastoma.

Laser interstitial thermal therapy (LITT) offers a minimally-invasive treatment option for glioblastomas (GBM) which are relatively small or in eloquent areas. While laser ablation for malignant gliomas has been shown to be safe and effective, the role of the subsequent immune response in not well established. In this study we aim to analyze the prognostic potential of edema volume and acute inflammation, quantified as neutrophil-to-lymphocyte ratio (NLR), in predicting overall survival. Twenty-one patients were identified with new or recurrent GBMs that were candidates for LITT. Laser ablation was performed using standard solid tumor protocol for treatment volume, intensity and duration. Edema volume was quantified using MRI imaging, while retrospective chart review was performed to calculate NLR and survival. In patients treated with LITT for GBM, peri-tumoral vasogenic edema volumes did not significantly change post-operatively, p > 0.200, while NLR significantly increased, p = 0.0002. The degree of NLR increase correlated with longer overall survivals, and ROC analysis demonstrated an area under the curve of 0.827, p = 0.0112. A delta-NLR cutoff of 7.0 results in positive and negative predictive values of 78% and 75%, respectively, in predicting overall survival >1 year. Patients with with delta-NLR > 7.0 lived significantly longer that those with delta-NLR < 7.0, median survival 440 days compared to 239 days, p = 0.0297. We demonstrate preliminary data that monitoring the inflammatory response after LITT in GBM patients offers a potential prognostic measurement to assist in predicting treatment efficacy and overall survival.

Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma.

PURPOSE: In the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens. METHODS: This bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment. RESULTS: Hematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy. CONCLUSIONS: This analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.

System-based approaches as prognostic tools for glioblastoma.

BACKGROUND: The evasion of apoptosis is a hallmark of cancer. Understanding this process holistically and overcoming apoptosis resistance is a goal of many research teams in order to develop better treatment options for cancer patients. Efforts are also ongoing to personalize the treatment of patients. Strategies to confirm the therapeutic efficacy of current treatments or indeed to identify potential novel additional options would be extremely beneficial to both clinicians and patients. In the past few years, system medicine approaches have been developed that model the biochemical pathways of apoptosis. These systems tools incorporate and analyse the complex biological networks involved. For their successful integration into clinical practice, it is mandatory to integrate systems approaches with routine clinical and histopathological practice to deliver personalized care for patients. RESULTS: We review here the development of system medicine approaches that model apoptosis for the treatment of cancer with a specific emphasis on the aggressive brain cancer, glioblastoma. CONCLUSIONS: We discuss the current understanding in the field and present new approaches that highlight the potential of system medicine approaches to influence how glioblastoma is diagnosed and treated in the future.

Second near-infrared photodynamic therapy and chemotherapy of orthotopic malignant glioblastoma with ultra-small Cu2-xSe nanoparticles.

The treatment of malignant glioblastoma is a huge challenge due to the existence of the blood-brain barrier. Herein, we report the treatment of orthotopic malignant glioblastoma with imaging guided second near-infrared (NIR-II) photodynamic therapy and chemotherapy by using drug-loaded ultra-small Cu2-xSe theranostic nanoparticles (NPs). Ultra-small Cu2-xSe NPs possess a strong absorbance in the NIR-II window, and their absorption at 1064 nm is around 2 times that at 808 nm. Their strong NIR-II absorbance and the deeper-tissue penetration of NIR-II light ensure excellent photodynamic therapy performance under irradiation with a 1064 nm laser. We also demonstrate that ultra-small Cu2-xSe NPs can produce vast amounts of reactive oxygen species via electron transfer (for ˙OH generation) and energy transfer (for 1O2 generation) mechanisms under irradiation. In addition, these NPs can be effectively and locally transported into orthotopic malignant glioblastoma with the assistance of focused ultrasound. The deposited Cu2-xSe NPs can be used for photoacoustic imaging to guide the combined NIR-II photodynamic therapy and chemotherapy. The results show that the tumor growth can be significantly suppressed. This work demonstrates the great potential of drug-loaded ultra-small Cu2-xSe NPs as a promising therapeutic agent for the treatment of orthotopic malignant glioblastoma.

A feasibility study of the Nativis Voyager® device in patients with recurrent glioblastoma in Australia.

AIM: Evaluation of the Nativis Voyager®, an investigational medical device, as monotherapy for recurrent glioblastoma (rGBM). MATERIALS & METHODS: A total of 15 patients with rGBM were treated with one of two Voyager ultra-low radio frequency energy cognates: A1A or A2HU. Safety and clinical utility were assessed every 2-4 months. RESULTS: Median overall survival was 8.04 months in the A1A arm and 6.89 months in the A2HU arm. No serious adverse events associated with Voyager were reported. No clinically relevant trends were noted in clinical laboratory parameters or physical exams. CONCLUSION: The data suggest that the Voyager is safe and feasible for the treatment of rGBM.

An early feasibility study of the Nativis Voyager® device in patients with recurrent glioblastoma: first cohort in US.

AIM: Evaluation of the Nativis Voyager® device in patients with recurrent glioblastoma (rGBM). MATERIALS & METHODS: Voyager is a noninvasive, nonthermal, nonionizing and portable investigational device which delivers ultra-low radio frequency energy (ulRFE®) that uses a magnetic field to penetrate tissues to alter specific biologic functions within cells. Patients with rGBM were treated with Voyager alone (V) or Voyager in combination with standard of care (V + SoC). Safety and clinical utility were assessed every 2-4 months. RESULTS: Data from the first 11 patients treated are reported here. Median progression-free survival was 10 weeks in the V arm and 16 weeks in the V + SoC arm. Median overall survival was 16 months in V arm and 11 months in the V + SoC arm. No serious adverse events associated with the device were reported. CONCLUSION: These data suggest that the Voyager is safe and feasible for the treatment of rGBM.

Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes.

BACKGROUND: Despite the multitude of available treatments, glioblastoma (GBM) remains an aggressive and uniformly fatal tumor. Laser interstitial thermal therapy (LITT) is a novel, minimally invasive treatment that holds promise for treating patients with GBM who are not candidates for traditional open craniotomy. However, due to the recent introduction of LITT into clinical practice, large series that evaluate safety and long-term outcomes after LITT are lacking. OBJECTIVE: To present our institution's series of over 50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes. METHODS: We performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data. RESULTS: We performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. Average percentage of tumor treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival 6.6 mo. CONCLUSION: LITT appears to be a safe and effective treatment for GBM in properly selected patients.

Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients.

AIM: To estimate the mean lifetime survival benefit, an essential component of health economic evaluations in oncology, of adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) for newly diagnosed glioblastoma patients. METHODS: We integrated EF-14 trial data with glioblastoma epidemiology data. The model provided for an evidence-based approach to estimate lifetime survival for the material number of EF-14 trial patients still alive at 5 years. RESULTS & CONCLUSION: Patients treated with TTFields and TMZ had an incremental mean lifetime survival of 1.8 years (TTFields/TMZ: 4.2 vs TMZ alone: 2.4). Patients alive at year 2 after starting TTFields had a 20.7% probability of surviving to year 10. The results presented here provide the required incremental survival benefit necessary for a future assessment of the incremental cost-effectiveness of TTFields.

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients' prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

Multiparametric MR Imaging of Diffusion and Perfusion in Contrast-enhancing and Nonenhancing Components in Patients with Glioblastoma.

Purpose To determine whether regions of low apparent diffusion coefficient (ADC) with high relative cerebral blood volume (rCBV) represented elevated choline (Cho)-to-N-acetylaspartate (NAA) ratio (hereafter, Cho/NAA ratio) and whether their volumes correlated with progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma (GBM). Materials and Methods This retrospective analysis was approved by the local research ethics committee. Volumetric analysis of imaging data from 43 patients with histologically confirmed GBM was performed. Patients underwent preoperative 3-T magnetic resonance imaging with conventional, diffusion-weighted, perfusion-weighted, and spectroscopic sequences. Patients underwent subsequent surgery with adjuvant chemotherapy and radiation therapy. Overlapping low-ADC and high-rCBV regions of interest (ROIs) (hereafter, ADC-rCBV ROIs) were generated in contrast-enhancing and nonenhancing regions. Cho/NAA ratio in ADC-rCBV ROIs was compared with that in control regions by using analysis of variance. All resulting ROI volumes were correlated with patient survival by using multivariate Cox regression. Results ADC-rCBV ROIs within contrast-enhancing and nonenhancing regions showed elevated Cho/NAA ratios, which were significantly higher than those in other abnormal tumor regions (P < .001 and P = .008 for contrast-enhancing and nonenhancing regions, respectively) and in normal-appearing white matter (P < .001 for both contrast-enhancing and nonenhancing regions). After Cox regression analysis controlling for age, tumor size, resection extent, O-6-methylguanine-DNA methyltransferase-methylation, and isocitrate dehydrogenase mutation status, the proportional volume of ADC-rCBV ROIs in nonenhancing regions significantly contributed to multivariate models of OS (hazard ratio, 1.132; P = .026) and PFS (hazard ratio, 1.454; P = .017). Conclusion Volumetric analysis of ADC-rCBV ROIs in nonenhancing regions of GBM can be used to identify patients with poor survival trends after accounting for known confounders of GBM patient outcome.

Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.

PURPOSE: Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes. EXPERIMENTAL DESIGN: Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels. RESULTS: hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136). CONCLUSIONS: Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.

The hedgehog antagonist HHIP as a favorable prognosticator in glioblastoma.

Inactivation of hedgehog-interacting protein (HHIP) and overexpression of Gli1 play vital roles in the development of diverse human cancers. The aim of this study is to examine the association of HHIP and Gli1 with the clinicopathologic features and prognosis of patients with glioblastoma (GBM). The expression of HHIP and Gli1 in 103 patients with GBM and 32 control patients was investigated by immunohistochemistry. Statistical analysis was utilized to evaluate the association of HHIP as well as Gli1 with clinicopathological characteristics and prognosis of patients. HHIP and Gli1 were dysregulated in GBM. Spearman's rank analysis showed that HHIP and Gli1 had an inverse correlation (r = -0.386, P = 0.000). Expression of HHIP was significantly correlated with age (P = 0.000), gender (P = 0.003), seizure (P = 0.013), resection degree (P = 0.033), adjuvant treatment (P = 0.030), and O(6)-methylguanine-DNA methyltransferase (MGMT) methylation (P = 0.021), while Gli1 expression was significantly correlated with age (P = 0.002), gender (P = 0.033), Karnofsky performance status (KPS) score (P = 0.028), resection degree (P = 0.000), adjuvant treatment (P = 0.014), and MGMT methylation (P = 0.030). Kaplan-Meier method showed that patients with low Gli1 expression had longer overall survival (OS) than those with high Gli1 expression (P = 0.000) and the OS of the patients with HHIP-positive GBM was significantly longer than that of the patients with HHIP-negative GBM (P = 0.000). Univariate and multivariate analyses confirmed that HHIP expression and Gli1 expression were independent prognostic factors. Our data suggested that expression of HHIP could be considered as significant prognostic marker for patients with GBM.

Prognostic relevance of epilepsy at presentation in glioblastoma patients.

BACKGROUND: Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients. METHODS: Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment. RESULTS: Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment. CONCLUSION: Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.