Recurrent Glioblastoma Multiforme Patients Research Articles

Nivolumab for newly and recurrent glioblastoma multiforme treatment: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis aiming to assess the efficacy and safety of Nivolumab treatment in patients with newly diagnosed and recurrent glioblastoma multiforme (GBM). Our study followed the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations. The protocol for this review can be found in the International Prospective Register of Systematic Reviews Database (CRD42022340071). We performed searches on the Medline, PubMed, Embase, Scopus, and Web of Science databases. A total of 545 studies were identified through our comprehensive search across the five databases (PubMed: 78, Embase: 82, Medline: 173, Scopus: 138, Web of Science: 74). After conducting a thorough analysis, our meta-analysis indicated that treatment with Nivolumab led to improved overall survival (OS) outcomes in newly diagnosed glioblastoma patients, as evidenced by a prolonged median OS based on trial data. However, there was no significant beneficial effect observed in terms of median progression-free survival (PFS), as well as OS at 6, 12, and 24 months. Furthermore, our results demonstrated no efficacy of Nivolumab in the treatment of recurrent GBM patients. In conclusion, Nivolumab demonstrated promising results that warrant further investigation for its use in newly diagnosed glioblastoma patients. However, its effectiveness was not observed in the context of recurrent GBM.

Should Redo Surgery be Offered to Patients with Relapsed Glioblastoma? - Outcome Analyses of a Single Institution Comparative Cohort Study

Glioblastoma multiforme (GBM) is the predominant malignant brain tumor originating intracranially. The established first-line treatment postsurgery is concurrent chemoradiation as a definitive measure. However, recurrent GBM's pose a challenge for clinicians who rely on institutional experience to determine the most suitable course of action. Second-line chemotherapy may be administered with or without surgery depending on the institution's practice. This study aims to present our tertiary center institution's experience with recurrent GBM patients who underwent redo surgery. In this retrospective study we analyzed the surgical and oncological data of patients with recurrent GBM who underwent redo surgery at the Royal Stoke University Hospitals between 2006 and 2015. The group 1 (G1) comprised the reviewed patients, while a control group (G2) was randomly selected, matching the reviewed group by age, primary treatment, and progression-free survival (PFS). The study collected data on various parameters, including overall survival, PFS, extent of surgical resection, and postoperative complications. This retrospective study included 30 patients in G1 and 32 patients in G2, matched based on age, primary treatment, and PFS. The study found that the overall survival for the G1 group from the time of first diagnosis was 109 weeks (45-180) compared to 57 weeks (28-127) in the G2 group. The incidence of postoperative complications after the second surgery was 57%, which included hemorrhage, infarction, worsening neurology due to edema, cerebrospinal fluid leak, and wound infection. Furthermore, 50% of the patients in the G1 group who underwent redo surgery received second-line chemotherapy. Our study found that redo surgery for recurrent GBM is a viable treatment option for a select group of patients with good performance status, longer PFS from primary treatment, and compressive symptoms. However, the use of redo surgery varies depending on the institution. A well-designed randomized controlled trial in this population would help establish the standard of surgical care.

Assessment of the Efficacy of an Alternative Regimen of Lomustine in Recurrent GBM – A Single Centre Experience

Abstract AIMS Lomustine (CCNU) based regimens are frequently used for recurrent glioblastoma multiforme (GBM). The usual CCNU regimen is 100-130mg/m2, day 1 x 6-weekly cycle for up to 6 cycles. Efficacy is limited, with median progression-free survival (PFS) approximating 1.0-3.0 months with higher haematological toxicities, particularly thrombocytopenia around 13-25%. The Clatterbridge Cancer Centre, UK, has adopted the regimen of 40mg once a day over 4 days x 4-weekly for up to 6 cycles. This study aims to identify the efficacy and toxicity profile of this regimen in recurrent GBM. METHOD A retrospective analysis on 113 recurrent GBM patients, treated with single-agent CCNU as a second-line, between June 2016 and January 2020. Kaplan-Meier survival estimates identified PFS, PFS at 6 months (PFS6) and Overall Survival (OS) using SPSS v.27. Overall Responses were based on imaging or clinical assessment in patients with at least 2 CCNU cycles. SACT assessments and blood test records, using CTCAE v5.0 grading, identified clinical adverse events. RESULTS We observed an 18.8% overall response rate with 2.4% partial response and 16.5% stable disease. There was a CCNU-specific 8-month median OS, 4-month median PFS, and 20.4%% PFS6. This regimen was well-tolerated. The most common toxicity was grade 1 fatigue (38.9%). The Grade 3 or 4 haematological toxicity was low with 12% thrombocytopenia and 2.7% neutropenia rates in patients. CONCLUSION This study suggests a reasonable alternative to the usual regimen, offering improved tolerance, lower toxicity rates, and equivalent efficacy. We propose prospective studies comparing differing CCNU regimens to mitigate retrospective studies’ limitations.

Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

Recycling of SLC38A1 to the plasma membrane by DSCR3 promotes acquired temozolomide resistance in glioblastoma.

Glioblastoma multiforme (GBM) is a primary brain tumor with devastating prognosis. Although the O6-methylguanine-DNA methyltransferase (MGMT) leads to inherent temozolomide (TMZ) resistance, approximately half of GBMs were sufficient to confer acquired TMZ resistance, which express low levels of MGMT. The purpose of this study was to investigate the underlying mechanisms of the acquired TMZ resistance in MGMT-deficient GBM. The function of Down syndrome critical region protein 3 (DSCR3) on MGMT-deficient GBM was investigated in vitro and in an orthotopic brain tumor model in mice. Purification of plasma membrane proteins by membrane-cytoplasmic separation and subsequent label free-based quantitative proteomics were used to identified potential protein partners for DSCR3. Immunofluorescence was performed to show the reverse transport of solute carrier family 38 member 1 (SLC38A1) mediated by DSCR3. DSCR3 is upregulated in MGMT-deficient GBM cells during TMZ treatment. Both DSCR3 and SLC38A1 were highly expressed in recurrent GBM patients. Silencing DSCR3 or SLC38A1 expression can increase TMZ sensitivity in MGMT-deficient GBM cells. Combination of proteomics and in vitro experiments show that DSCR3 directly binds internalized SLC38A1 to mediate its sorting into recycling pathway, which maintains the abundance on plasma membrane and enhances uptake of glutamine in MGMT-deficient GBM cells. DSCR3 is a crucial regulator of acquired TMZ resistance in MGMT-deficient GBM. The DSCR3-dependent recycling of SLC38A1 maintains its abundance on plasma membrane, leading to tumor progression and acquired TMZ resistance in MGMT-deficient GBM.

C-X-C Motif Chemokine Ligand 6: A Preoperative Biomarker for Recurrent Glioblastoma Multiforme

To explore the function of C-X-C motif chemokine ligand as a prospective early biomarker for recurrent glioblastoma multiforme is the objective of the study. The differentially expressed genes for glioblastoma multiforme patients were systematically explored; the gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis for potential hub gene was established; the functional network was developed by protein-protein interaction method. The glioblastoma multiforme cell line U251 was established for the in vitro functional experiments; the wound healing assay as well as transwell assay were conducted to measure tumor properties in U251 cells. The expression of C-X-C motif chemokine ligand 6 in recurrent patients of glioblastoma multiforme was significantly higher than in non-recurrent patients (p<0.05), suggesting C-X-C motif chemokine ligand 6 was an independent prognostic indicator for glioblastoma multiforme recurrence. Based on the gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis as well as a protein-protein interaction network for the C-X-C motif chemokine ligand 6, programmed death ligand-1 and signal transducer and activator of transcription 3 signaling were primarily associated with C-X-C motif chemokine ligand 6. C-X-C motif chemokine ligand 6 over-expression treatments induced markedly enhanced expression levels for programmed death ligand-1 and phospho-signal transducer and activator of transcription 3. At the same time, the regulation of C-X-C motif chemokine ligand 6 for U251 cells tumor properties was programmed death ligand-1 dependent since silencing of programmed death ligand-1 obviously attenuated the functions of C-X-C motif chemokine ligand 6 over-expression. Moreover, it could be implied that the expression levels of programmed death ligand-1 and phospho-signal transducer and activator of transcription 3 were linked to the recurrent status of glioblastoma multiforme patients, as their expression was remarkably accelerated for recurrent glioblastoma multiforme patients. This integrated study provided a potential biomarker and offered beneficial references for future clinical administration as well as evaluation of recurrent glioblastoma multiforme.

Development and in vivo evaluation of Irinotecan-loaded Drug Eluting Seeds (iDES) for the localised treatment of recurrent glioblastoma multiforme

Glioblastoma multiforme (GBM) is impossible to fully remove surgically and almost always recurs at the borders of the resection cavity, while systemic delivery of therapeutic drug levels to the brain tumour is limited by the blood-brain barrier. This research describes the development of a novel formulation of Irinotecan-loaded Drug Eluting Seeds (iDES) for insertion into the margin of the GBM resection cavity to provide a sustained high local dose with reduced systemic toxicities. We used primary GBM cells from both the tumour core and Brain Around the Tumour tissue from recurrent GBM patients to demonstrate that irinotecan is more effective than temozolomide. Irinotecan had a 75% response rate, while only 50% responded to temozolomide. With temozolomide the cell viability was never below 80% whereas irinotecan achieved cell viabilities of less than 44%. The iDES were manufactured using a hot melt extrusion process with accurate irinotecan drug loadings and the same cytotoxicity as unformulated irinotecan. The iDES released irinotecan in a sustained fashion for up to 7 days. However, only the 30, 40 and 50% w/w loaded iDES formulations released the 300 to 1000 μg of irinotecan needed to be effective in vivo. The 30 and 40% w/w iDES formulations containing 10% plasticizer and either 60 or 50% PLGA prolonged survival from 27 to 70 days in a GBM xenograft mouse resection model with no sign of tumour recurrence. The 30% w/w iDES formulations showed equivalent toxicity to a placebo in non-tumour bearing mice. This innovative drug delivery approach could transform the treatment of recurrent GBM patients by improving survival and reducing toxicity.

Novel approaches to combat chemoresistance against glioblastomas.

The poor prognosis of glioblastoma multiforme (GBM) patients is in part due to resistance to current standard-of-care treatments including chemotherapy [predominantly temozolomide (TMZ; Temodar)], radiation therapy and an anti-angiogenic therapy [an antibody against the vascular endothelial growth factor (bevacizumab; Avastin)], resulting in recurrent tumors. Several recurrent GBM tumors are commonly resistant to either TMZ, radiation or bevacizumab, which contributes to the low survival rate for GBM patients. This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance. One of these therapeutic options is a small molecule called OKlahoma Nitrone 007 (OKN-007), which was discovered to inhibit the transforming growth factor β1 pathway, reduce TMZ-resistance and enhance TMZ-sensitivity. OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients. Another novel target is ELTD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1; alternatively known as ADGRL4, Adhesion G protein-coupled receptor L4), which we used a monoclonal antibody against, where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model. Notch 1 is known to be associated with chemoresistance in GBM. Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway, nuclear factor-κB, the hepatocyte/scatter factor (c-MET), the epidermal growth factor receptor, and the tumor microenvironment.

Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune® System.

Background:Tumor treating fields (TTFields) are a non-invasive antimitotic therapy that delivers alternating electric fields via the Optune® system. The Phase III EF-14 trial in newly diagnosed glioblastoma multiforme (GBM) showed significantly improved progression-free, overall and long-term survival when Optune was used together with maintenance temozolomide (TMZ) compared with TMZ alone. Compliance (average monthly use) was associated with better clinical outcome. The first-generation Optune system weighed approximately 6 pounds (~2.7 kg). The second-generation redesigned Optune system weighs 2.7 pounds (~1.2 kg). We tested and compared GBM patient experience with the second-generation system versus the first-generation system.Methods:Ten newly diagnosed and recurrent GBM patients in Germany (median age: 52.9 years [31-79]) were prospectively monitored over the first month of transitioning from the first-generation to the second-generation Optune system. Questionnaires using a numerical analog scale assessed feedback at baseline (first generation) and after 1 month of second-generation use.Results:After transitioning to the second-generation system, compliance improved by more than 10% in four patients, was maintained in five patients and decreased by more than 10% in one patient. Following transition, eight out of nine patients reported a reduction in the triggering of malfunction alarms. Self-reported patient feedback showed improved handling and portability (weight, mobility) of the second- versus the first-generation Optune system.Conclusions:This patient user survey suggests that patient satisfaction with the second-generation Optune system is improved versus the first-generation system. Improved features of the new system help patients achieve and maintain a higher rate of treatment compliance.

RECURRENT GLIOBLASTOMA MANAGEMENT USING STEREOTACTIC RADIOSURGERY AND SYSTEMIC TREATMENT

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system in adults. Dismal survival rates and poor prognosis for recurrent GBM patients still remains a challenging problem. Despite aggressive initial treatment, above 100 % GBM patients have development of recurrent diseases. Management of GBM recurrence is still debatable. The multimodality approaches using combination of stereotactic radiosurgery (SRS), cytostatic agents (Тemozolomide (TMZ)) and antiangiogenic therapy (bevacizumab (BEV)) are often beneficial for such patients and may achieve survival improving. Aim of research: to assess the efficacy and toxicity of combination therapy approach using stereotactic radiosurgery (SRS) and systemic treatment (chemotherapy and antiangiogenic therapy) in glioblastoma multiforme recurrence treatment. Materials and methods: at the State Institution “Institute of Neurosurgery named after acad. A.P. Romodanov of NAMS of Ukraine” (Kyiv, Ukraine) 21 patients (pts) with GBM recurrence were treated (8 females and 11 men; median age at time of diagnosis 52.4 (29.7–69.3) from January 2014 till December 2017. The initial surgical treatment as gross total tumor resection was performed in 12 pts (57.1 %), subtotal resection – 5 pts (23.9 %), biopsy – 4 pts (19 %). 12 pts (57.1 %) were MGMT methylated and 9 pts (42.9 %) were MGMT unmethylated. In all cases adjuvant radiation therapy (60 Gy in 30 fractions) were used, 12 pts of them (57.1 %) – in combination with TMZ followed by 6-12 courses of chemotherapy (TMZ) according Stupp protocol. Recurrent disease was treated by SRS followed by TMZ + BEV. SRS was performed by means of “Trilogy” LINAC (“Varian”, USA) with a median dose and fractions of 19.2 Gy (range, 12.0–36.0) in 1 to 5 fractions. Results: median survival after initial diagnosis was 18.3 months, and 1- and 2-year survival rates of 85.7 % (18 from 21 pts) and 38.1 % (8 from 21 pts) respectively. The median survival from the time of recurrence treatment was 8.3 months. The 6‐ and 12‐months overall survival from SRS were 95.2 % (20 from 21 pts) and 23.8 % (5 from 21 pts), respectively. Adverse radiation effects were noted in 6 (28.6 %) pts and were controlled with corticosteroids. Adverse events grade 1-2 related to the systemic therapy included hematological complications, fatigue, hypertension and proteinuria were observed in 23.8 % (5 from 21 pts) without the occurrence of grade 3 events. Conclusion: recurrent GBM management using combination of SRS, chemotherapy and antiangiogenic therapy is a promising multimodal treatment approach providing survival improving whereas appropriate toxicity ratio. Further studies of combined treatment of GBM relapse are needed.

389P - Bevacizumab-induced hypertension correlation with survival in recurrent glioblastoma multiforme

Background: Patients with Glioblastoma multiforme (GBM) have a poor prognosis and therapeutic options are scarce after recurrence. Bevacizumab (Bv) is approved for use in this setting with proven benefits in progression-free survival (PFS) but not in overall survival (OS). Arterial hypertension (HT), a well described side effect of Bv, has been proposed as a predictive marker of clinical response in GBM as well as in other neoplasms, though conflicting data is available. This study tried to evaluate the prognostic impact of HT and other factors in recurrent GBM. Methods: Retrospective cohort of adult patients with recurrent GBM treated with a combination of Bv + Irinotecan (BvI) or Lomustine (BvL) between 01/01/2009 and 31/12/2017. Clinical records were analysed. Bv-induced HT was defined as a single evaluation ≥140/90 mmHg during first 3 months of treatment or the need to initiate or increase dose of antihypertensive drugs. OS and PFS were estimated by Kaplan-Meier method and multivariate analysis according to Cox regression; a significant level of 0.05 was chosen to assess the statistical significance. Results: 120 patients were included with male gender predominance (64.2%) and a median age at Bv onsent of 58.7 (27-78 yo). All patients were treated in first line with surgery (complete resection: 61.7%; partial resection: 38.3%) and Stupp protocol. BvI was used in 70.8% (n = 85) and BvL in 29.2% (n = 35) patients. Bv-induced HT was found in 29% of patients (n = 29) and proteinuria (PU) in 15% (n = 18). Median PFS was 4.4 months (mo) (CI 95% 3.5-5.4) and median OS was 7.8 mo (CI 95% 6.8-87). In multivariate analysis (Table), both HT and PU had an impact in PFS. OS was significantly prolonged in patients with HT and in those without corticosteroids (CCS) at Bv.Table: 389PPFS (mo)HR (CI 95%)OS (mo)HR (CI 95%)HTYes9.1HR 1.825 (1.136-2.931), p = 0.01314HR 2.726 (1.325-5.608), p = 0.006No4.17.8PUYes6.1HR 2.341 (1.282-4.275), p = 0.006--No3.9-CCS at Bv onsetYes--6.9HR 2.022 (1.059-3.860), p = 0.033No-13.4 Open table in a new tab Conclusions: In recurrent GBM patients treated with Bv combinations, HT was significantly related with prolonged PFS and OS. PU and the need for CCS also showed a significant prognostic impact. Legal entity responsible for the study: Serviço de Oncologia Médica - Centro Hospitalar de São João, EPE. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

LncRNA NEAT1 is involved in temozolomide resistance by regulating MGMT in glioblastoma multiforme

Introduction: As one of the most aggressive and lethal tumors, glioblastoma multiforme (GBM) is commonly treated by surgical resection combined with radiotherapy and chemotherapy. Temozolomide (TMZ) is the preferred chemotherapy medicine against GBM. However, recurrent GBM patients exhibit TMZ resistance. As reported in previous studies, NEAT1 is over-expressed in glioma cells; thus, we explored the relationship between NEAT1 and TMZ resistance in GBM. Materials and Methods: The expression levels of NEAT1 and O -6-methylguanine-DNA methyltransferase (MGMT) in GBM tissues and cells were determined by quantitative real-time PCR. Si-RNA and the over-expression vector were transfected into GBM cells to modulate the level of related molecules. Western blot analysis was used to investigate the protein expression of MGMT. The cell viability and IC-50 were analyzed by CCK-8, and apoptosis was detected by flow cytometry assay. Result: The expression level of NEAT1 in the TMZ-sensitive GBM tissues and cells was lower than that in the TMZ-resistant GBM tissues and cells. Furthermore, due to the down-regulation of NEAT1 in TMZ-resistant GBM cells transfected with Si-RNA, the viability and IC-50 value of the GBM cell lines were decreased, and the knockdown of NEAT1 significantly enhanced TMZ-induced cell apoptosis in GBM cells. We also determined that the mRNA and protein level of MGMT were up-regulated in TMZ-resistant GBM cells. Interference with MGMT expression led to a decrease in viability and IC-50 value in the GBM cells, and the knockdown of NEAT1 suppressed the transcription and translation levels of MGMT. However, the over-expression of MGMT enhanced TMZ resistance in NEAT1-silenced U87 and U251 cells. Conclusion: NEAT1 participates in the TMZ resistance of GBM cells by regulating MGMT.

Abstract CT141: Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Materials and Methods: Tumor treating fields (TTFields) therapy is a novel treatment technique that has recently shown significant prolonged progression free survival and overall survival innewly diagnosed GBM. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. Results: Our center was the first in the world to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 12 years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment. Conclusions: Our results indicate that TTField treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. Further investigation is needed to identify any unique characteristics of these patients. We recommend that TTField treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment. Citation Format: Aaron Rulseh, Jan Šroubek, Jan Klener, Josef Vymazal. Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT141. doi:10.1158/1538-7445.AM2017-CT141

The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review.

BackgroundCurrently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.MethodsTrials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).ResultsA total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38–6.21; p = 0.025; and RR 2.36 95% CI 1.46–3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64–17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.ConclusionsIn comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.

Abstract 4306: A prognostic model for clinical response to bevacizumab in recurrent glioblastoma multiforme

Abstract Background: Recurrent glioblastoma multiforme (GBM) is an aggressive and deadly disease with limited treatment options. In responding patients bevacizumab-containing therapy prolongs survival and improves quality of life, although the beneficial effect varies greatly. The impact of prognostic factors in recurrent GBM patients has not been studied in detail and results are inconsistent. More importantly, no validated predictive baseline markers associated with a clinical response to bevacizumab therapy have been identified. Furthermore, GBM is a very heterogenic tumor and has been shown to change molecular pattern with time and as a result of treatment. The primary goal of this study was to describe molecular characteristics in GBM tumors at initial diagnosis and at recurrence and relate these data, including clinical baseline factors, to clinical outcome with the aim of identifying predictive factors for clinical bevacizumab response. Based on these data we will also elucidate to what extent molecular markers change expression from initial GBM diagnosis to time of relapse. Materials and Methods: For generation of prognostic models 219 recurrent GBM patients treated with bevacizumab plus irinotecan according to a previous published clinical protocol were included. For biomarker analysis, routine molecular analyses were available for 147 of the included patients at time of initial diagnosis and 81 patients at time of relapse prior to bevacizumab therapy. The candidate biomarkers constituted an immunohistochemistry (IHC) panel of EGFR, P53, MGMT and IDH1 and polymerase chain reaction analysis of 1p19q-status. Tumor samples from initial diagnosis and from time of relapse were analyzed by the χ2 test and the Wilcoxon test in order to evaluate changes in IHC expression patterns. Multiple candidate prognostic factors were screened by univariate logistic regression and Cox regression analysis modeling response and survival endpoints and variables with P-values of less than 0.10 were considered for multivariate analysis. Factors with a P-value of less than 0.05 in multivariate analysis were included in the prognostic models for response, progression-free survival (PFS) and overall survival (OS). Results: In multivariate analysis, corticosteroid use had a negative predictive impact on response at first evaluation (OR = 0.45; 95% CI: 0.22-0.93; P = 0.030) and at best response (OR = 0.51; 95% CI: 0.26-1.02; P = 0.056). Independent prognostic factors (P&amp;lt;0.05) negatively associated with PFS and OS were corticosteroid use, neurocognitive deficit and multifocal disease. Based on the three identified factors a prognostic model for overall survival at 6 and 12 months was developed. Significant prognostic and potentially predictive molecular biomarkers will be added to the models and results will be presented. Citation Format: Thomas Urup, Signe Regner Michaelsen, Camilla Bjørnbak Holst, Anders Toft, Ib Jarle Christensen, Kirsten Grunnet, Michael Kosteljanetz, Helle Broholm, Ulrik Lassen, Hans Skovgaard Poulsen. A prognostic model for clinical response to bevacizumab in recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4306. doi:10.1158/1538-7445.AM2015-4306

Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30–40% response rate, many fall into the range of 10–20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity

Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1–4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients.Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine®), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide.Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330).

Retrospective analysis of bevacizumab in combination with fotemustine in chinese patients with recurrent glioblastoma multiforme.

The aim of this study was to assess the activity and safety of bevacizumab (BEV) and fotemustine (FTM) for the treatment of recurrent glioblastoma multiforme (GBM) patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 90.9%, respectively. A 6-month PFS rate of 33.3% (95% CI: 26.5%–40.3%) and a median PFS of 5.0 (95% CI: 2.4–7.5) months were observed. The median OS was 8.0 (95% CI: 6.7–9.2) months. Multivariate analysis showed that risk factors with a significant influence on the PFS of all patients were Karnofsky Performance Status (KPS) (≥70 versus <70, HR = 0.53, 95% CI: 0.39–0.73, and P = 0.01) and MGMT status (methylated versus unmethylated, HR = 0.69, 95% CI: 0.52–0.97, and P = 0.04). The most common treatment-related adverse events were fatigue, proteinuria, hypophonia, hypertension, thrombocytopenia, anemia, and neutropenia. In conclusion, combination of BEV with FTM is well tolerated and may derive some clinical benefits in recurrent GBM patients. Higher KPS and MGMT promoter hypermethylation were suggested to be associated with prolonged survival.

Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe)

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.

Response Patterns of Recurrent Glioblastomas Treated With Tumor-Treating Fields

Glioblastoma multiforme (GBM) is the most common form of primary malignant brain cancer. Median overall survival (OS) for newly diagnosed patients is only about 12 to 18 months. GBM tumors invariably recur, and there is no widely recognized and effective standard treatment for recurrent GBM. NovoTTF Therapy is a novel and US Food and Drug Administration (FDA)-approved antimitotic treatment for recurrent GBM with potential benefits compared with other options. Recurrent GBM patients from two prior trials with demonstrated radiologic tumor response to single-agent NovoTTF Therapy were analyzed to better characterize tumor response patterns and evaluate the associations between response, compliance, and OS. In addition, a compartmental tumor growth model was developed and evaluated for its ability to predict GBM response to tumor-treating fields (TTFields). The overall response rate across both trials was 15% (4% complete responses): 14% in the phase III trial (14/120) and 20% (2/10) in a pilot study. Tumor responses to NovoTTF Therapy developed slowly (median time to response, 5.2 months) but were durable (median duration, 12.9 months). Response duration was highly correlated with OS (r(2) = .92, P<.0001), and median OS for responders was 24.8 months. Seven of 16 responders exhibited initial tumor growth on magnetic resonance imaging. Compliance appeared to be linked with both improved response and survival. The tumor growth model predicted tumor arrest and shrinkage only after several weeks of continuous NovoTTF Therapy, consistent with the observed clinical findings of initial transient tumor growth in some patients. NovoTTF Therapy is a novel antimitotic treatment for recurrent GBM associated with slowly developing but durable tumor responses in approximately 15% of patients. Some responders exhibit initial tumor growth before shrinkage, indicating treatment should not be terminated prior to allowing for the full effect of NovoTTF Therapy to be realized. OS is longer in responders than in nonresponders. High daily compliance rates may be associated with increased likelihood of an objective response and are predictive of improved survival.