Treatment Of Recurrent Malignant Gliomas Research Articles

Survival after stereotactic radiosurgery of recurrent glioblastomas in patients with radical resection of primary tumor

glioblastoma (GBM) is an aggressive tumor with high rate of recurrence and estimated survival of 15-18 months after diagnosis. Factors associated with longer survival of GBM patients are age < 50 years, high performance status and radical resection of the primary tumor. The optimal treatment for recurrence/ progression of GBM has not yet been determined and remains a challenging issue. Stereotactic radiosurgery (SRS) is considered today as a therapeutic option for effective treatment of recurrent malignant gliomas. The aim of this retrospective study was to analyze the survival after SRS of the recurrent GBM in a cohort of 59 patients, which had a radical resection of the primary tumor. The cohort consisted of 59 patients (28 / 47.5% of women and 31 / 52.5% of men); the average age was 51 years (interval 24 - 81). SRS was performed by means of linear accelerator "Trilogy" (USA) (6 MeV) from 2014 to 2020 at the State Institution "Romodanov Neurosurgery Institute". In all cases, the diagnosis of grade 4 GBM according to the WHO classification was confirmed after neurosurgical procedures of the primary tumor. All 59 patients underwent the maximal safe removal of the primary tumor: in the vast majority of cases (54 / 91.5%) - in the perifocal area; in 5 / 8.5% of cases - subtotal. In all 59 cases, patients received adjuvant radiation therapy (total dose 60 Gy in 30 fractions); in 33 / 55.9% of cases radiotherapy was combined with concomitant alkylating chemotherapy (CHT) (Temozolomide 75 mg / m2). In 31 / 52.5% of patients, maintenance alkylating CHT was continued (Temozolomide 150-200 mg / m2). In most cases (51 / 86.4%) recurrent GBM (RGBM) was diagnosed by clinical and radiological signs; in 8 / 13.6% of patients - after repeated surgery. Overall survival (OS), recurrence/progression free survival (RFS) and survival after recurrence (SAR) represented the end-points of the study. The effect of the following quantitative and categorical factors (covariates) on the survival was studied: sex, age, performance status, combination of adjuvant RT with alkylating chemotherapy, neurosurgical procedures of RGBM, type of GBM recurrence, total dose of irradiation (BED11) and SRS dose (BED11), number of SRS fractions, volume of target in SRS, duration of RFS. The effect of RFS was studied in three independent groups: group I – RFS < 10 months; group II – RFS from 10 to 20 months; group III – RFS > 20 months. The survival was analyzed by Kaplan-Meier (KM) method. Log-rank test was used for analysis of the survival according to the binary predictors. The effect of several categorical factors on survival was analyzed by Pearson Chi-square test. The effect of the quantitative covariates on survival was studied by regression analysis in Cox proportional risk model. Hazard ratio was calculated with 95 % confidential intervals (CI). The analysis revealed the following. Median OS following SRS RGBM was 26.3 months (95 % CІ 17 – 45.5), median RFS was 12.9 months (95 % CІ 8.4 – 25.6), median SAR – 9.8 months (95 % CІ 6.7 – 24.4). Two-year OS in our study was 56 %. 6-month survival after SRS –77 %; one-year survival after SRS – 39 %, and two-year survival after SRS – 28 %. The significant impact of performance status (p = 0.00159), duration of recurrence-free period (p = 0.02711) and surgical resection of RGBM (р = 0.009391) on the OS was demonstrated. The best OS was shown for the patients with Karnofsky score 90, recurrence occurring after more than 20 months and previous surgical resection of RGBM. The effects of other factors on OS were not demonstrated. Such factors as age, sex, performance status, adjuvant RT with сoncomitant alkylating CHT, surgical resection of RGBM, type of recurrence, number of SRS fractions, BED11 in SRS RGBM, BED11 for overall courses of irradiation, SRS target volume demonstrated no effect on SAR. SRS is non-invasive method for RGBM treatment that allows for improving the survival without significant radiation toxicity. Primary biological properties of the tumor seem to be of priority in determining the survival of RGBM patients. Although irradiation of GBM is advantageous regarding the improvement of the survival, one could also speculate that re-irradiation of the recurrent malignant glioma triggers some changes in its biology neutralizing the potential effect of the survival factors that had predictive value before re-irradiation.

Effect of temozolomide combined with radiotherapy on survival and MGMT protein expression in recurrent malignant glioma patients

Purpose: To investigate the effect of temozolomide (TMZ) combined with radiotherapy (RT) on O-6- methylguanine-DNA methyltransferase (MGMT) protein and survival of recurrent malignant glioma patients.
 Methods: Ninety-two patients with malignant glioma in our hospital from January 2014 to January 2015 were assigned to study and control groups using the random table method. Subjects in the control group received radiotherapy (total dose in the range of 60 – 75 Gy), while those in the study group were given TMZ orally (75 mg/m2) daily in addition to radiotherapy, as well as TMZ at 150 – 200 mg/m2. After treatment, clinical effectiveness was compared for the two groups. Changes in methylation of MGMT gene were determined in the two groups. The patients were followed up for 3 years, and the degrees of survival and recurrence were recorded.
 Results: Total effectiveness of clinical treatment was markedly higher in the study group (76.09 %) than in the control group (45.65 %; p < 0.05). One month after radiotherapy, significant decrease in MGMT gene methylation was seen in patients in the study group, relative to control patients (p < 0.05). Patients in the study group had lower median recurrence but higher degree of survival in the 2nd and 3rd years, relative to control patients (p < 0.05).
 Conclusion: The combination of temozolomide and radiotherapy is more effective than radiotherapy in the treatment of recurrent malignant glioma. The combined treatment significantly inhibits tumor recurrence in patients, and improves their prognosis and standard of life.

ACT-15 AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA

INTRODUCTIONMalignant gliomas are one of the most common and aggressive intracranial neoplasms in humans. Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is reduced in a variety of human cancer cells. We previously showed the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, we have also developed a novel adenoviral vector expressing REIC/Dkk-3 (Ad-SGE-REIC). We assessed the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma.MATERIALS AND METHODSWe evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan-Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial.RESULTSThe treatment with Ad-SGE-REIC showed the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC significantly prolonged survival time more than those treated with other vectors. A cGMP product of Ad-SGE-REIC was developed and supplied by a startup biotech company, Momotaro-Gene Inc. We conducted GLP toxicology tests using the intracranial injection of higher doses of Ad-SGE-REIC at Shin Nippon Biomedical Laboratories (SNBL Japan). After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma with our academic research organization (ARO), supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by our institution review board in March 2019. We submitted a notification of this trial in April 2019.CONCLUSIONSWe demonstrated the anti-glioma effect of Ad-SGE-REIC. We start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma (https://jrct.niph.go.jp/en-latest-detail/jRCT2063190013).

ATIM-21. THE CURRENT STATUS OF AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA

Abstract INTRODUCTION Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was reported to be reduced in a variety of human cancer cells. We previously examined the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, a novel adenoviral vector expressing REIC/Dkk-3 has also been developed based on the cytomegalovirus promoter-driven super gene expression system (Ad-SGE-REIC). We evaluated the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma. MATERIALS AND METHODS We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan–Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial. RESULTS In the cytotoxicity assay, after treatment with Ad-SGE-REIC, the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC survived significantly longer than those treated with other vectors. We also performed GLP toxicology tests using intracranial injection of higher doses of Ad-SGE-REIC in rats at Shin Nippon Biomedical Laboratories (SNBL Japan) to determine the injection dose of Ad-SGE-REIC for this clinical trial. After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by institution review board (IRB) in March 2019. We submitted a notification of this trial in April 2019. CONCLUSIONS We demonstrated the anti-glioma effect of Ad-SGE-REIC. We will start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma.

Phase I study of procaspase activating compound -1 (PAC-1) in combination with temozolomide (TMZ) for the treatment of recurrent malignant glioma.

TPS3164 Background: The caspase family of cysteine proteases play key roles in the initiation and execution of apoptosis. The activation of procaspase-3 to caspase-3 is critical in both the intrinsic and extrinsic apoptotic cascades. Procaspase-3 levels are elevated in many cancers, including glioblastoma (GBM). As a result, caspase-3 levels are abnormally low in these tumors; thus they avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 has activity against a wide range of cancer cell lines, and in animal models of cancer. PAC-1 crosses the blood brain barrier and has been shown to synergize with TMZ in both canine malignant glioma and meningioma that arise spontaneously. Methods: This Phase I dose escalation study uses a modified- Fibonacci 3+3 design to determine the MTD of PAC-1 when combined with TMZ in patients with recurrent malignant gliomas: anaplastic astrocytoma (AA) and GBM (open to enrollment). Here, we focus on component 2 of the study. Primary objectives: to establish MTD of PAC-1 when combined with a fixed dose of TMZ, tolerability, and toxicity using CTCAE v.4. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary anti-tumor activity correlation with procaspase-3 expression in tumor tissue, radiographic response using the Response Assessment in Neuro-Oncology (RANO) criteria, and neurocognitive function using a validated test battery. Inclusion criteria: diagnosis of recurrent high grade glioma (AA or GBM), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design, Component 2: PAC-1, orally administered, is dosed at 375-650 mg daily (up to 3 dose levels) on days 1-21 of each 28-day cycle. A fixed dose of TMZ, (150 mg/m2), is administered orally, days 8 -12 of each cycle. The study is currently enrolling patients for Component 2. Clinical trial information: NCT02355535.

Surgery for recurrent high-grade gliomas: the dilemma of debate

Abstract Background: Treating recurrent gliomas is a big dilemma in the literature and no uniform protocol is approved to treat such disappointing problem. Although improvement in the RT techniques, new CTX techniques and new techniques including targeted therapy and gene therapy; all fail to dramatically improve the outcome and solve the problem of significant mass effect when the recurrent tumor is big So resurgery play a role in treating such challenging problem. The aim of the study: to assess the goal and outcome of surgery in treatment of recurrent malignant glioma. Methods: We retrospectively analyzed the data of 56 patients who were operated upon for recurrent or progressed high grade gliomas in the Mansoura neurosurgery department allover 2007 to 2016. We have excluded patients with recurrent thalamic gliomas and patients with Kps score less than 70. Results: 12 patient underwent sterotactic biopsy for their tumor and were sent for adjuvant radiotherapy, 29 patients underwent partial tumor resection and gross total resection was done in 15 patients. The median time to progression was 5 months. All patients were sent after surgery for poster radiotherapy and chemotherapy. The median overall survival was 4 months. Conclusion: Recurrent high grade glioma is one of unsolved problem and optimal management is no longer available. Redo surgery is quiet challenging with higher minorities and no add to overall survival. Surgery is indicated to relieve significant mass effect. Outcome of surgery is better for those who did aggressive surgical resection at initial surgery than those who did only partial resection.

Retrospective analysis to evaluate the efficacy and the safety of Bevacizumab in the treatment of recurrent malignant gliomas

BackgroundThere is no consensus therapy recommended for recurrent malignant gliomas (MGs). In 2009, Bevacizumab (BEV) was approved by the FDA as single-agent for recurrent glioblastoma (GBM). The aim of this retrospective study was to evaluate the efficacy and the safety of BEV alone or in combination with Fotemustine (FTM) in recurrent MGs. This represents an interim analysis of a larger study on BEV in MGs patients.MethodsWe analyzed 17 recurrent MGs patients, 12 GBM (70.6%) and 5 anaplastic gliomas (29.4%), underwent first-line therapy with Stupp regimen. BEV was administered as off-label therapy, at a dose of 10 mg/kg every 14 days, in 13 patients as third-line therapy and in 4 patients as second-line therapy associated with FTM. The assessment of MGMT methylation and IDH1 mutation was conducted.ResultsOne complete response (5.9%), 7 partial responses (41.2%), 3 stable diseases (17.6%) and 6 progression diseases (35.3%) were assessed using RANO criteria. Median PFS (mPFS) and OS (mOS) were 5 and 8.3 months respectively, with a 6 months-PFS of 41.2%. Methylated patients and wild-type IDH1 patients showed longer mPFS and mOS without statistical significance. Six patients (35.3%) experienced long response with high number of cycles (11-40), long PFS (11-40 months) and OS (12-42 months). BEV was well-tolerated with grade 1-2 proteinuria and hypertension in 53% and 47.1% of patients respectively. Only one patient developed grade 3 proteinuria after 30 cycles and another one developed pulmonary embolism. No other grade 3-4 toxicities were observed.ConclusionsThis retrospective study showed the efficacy and the safety of BEV alone or in association with FTM in the treatment of MGs.The protocol (No: Beva-Glio/Sep 2016).

Assessment of Concurrent Stereotactic Radiosurgery and Bevacizumab Treatment of Recurrent Malignant Gliomas Using Multiparametric MRI Imaging and Radiomics Analysis

To assess the response and predict the overall survival (OS) of recurrent malignant gliomas (MG) patients treated with concurrent BVZ/SRS using multi-modality MRI imaging and radiomics analysis.Methods and materials: SRS was delivered in a single fraction (18/24Gy) or 25Gy in 5 fractions. BVZ was administered immediately before SRS and 2 weeks after. MRI scans were performed before SRS, 1 week and 2 months after SRS. The MR protocol included 2 anatomical (T1w and T2w) and 2 functional (dynamic contrast-enhanced DCE-MRI and diffusion weighted DW-MRI) modalities. Functional biomarkers including apparent diffusion coefficient (ADC), micro-vascular transfer constant Ktrans, brain blood flow FB, and blood volume VB were analyzed. Radiomics analysis was performed to extract imaging features from anatomical MRI images and functional biomarker maps. Wicoxon signed rank tests were performed to evaluate treatment-induced changes, and Mann-Whitney U tests were performed to compare the differences of treatment-induced changes between different patient groups. Selected biomarkers and radiomics features were used to predict the OS after treatment using Support Vector Regression (SVR) with leave-one-out cross validation (LOOCV).Twelve patients with recurrent MG were studied. The median OS was 13.8 months post SRS. DCE results showed that Ktrans (p=0.035) and VB (p=0.035) showed significant decrease 2 months after SRS, and FB showed significant decrease as early as 1 week (p=0.017) after SRS. No functional parameters reflected statistically significant treatment response 1 week after SRS. A total of 888 radiomics features were extracted. 31/126 features demonstrated significant changes 1 week/2 months after SRS, respectively. 9 features' changes were significantly different between WHO Grade III vs IV patient groups, and 6 features' changes were found to be linearly correlated with OS. Using 5 selected features, 9 patients' survival time could be accurately predicted (Mean absolute error = 1.47 months, RMSE = 2.10 months).The results of this work demonstrate the potential of combined radiomics analysis and functional MR imaging in quantitatively identifying early treatment response of concurrent SRS/BVZ.

Preliminary discussion of BCNU-loaded biodegradable implants for recurrent malignant gliomas

Objective To evaluate the safety and primary efficacy of BCNU-loaded biodegradable implants for the treatment of recurrent malignant gliomas. Methods From January 2011 to December 2012, 22 patients with recurrent malignant glioma treated at the Department of Neurosurgery, Sun Yat-sen University Cancer Center and the Department of Neurosurgeries of 5 hospitals in China were analyzed retrospectively. The BCNU-loaded implants were placed into the tumor cavities after surgical resection of gliomas. The adverse reactions of the patients within 28 d after procedure were documented in detail. Its safety was evaluated. The survival time and the efficacy of preliminary drug evaluation after placing the implants in patients were recorded. Results A total of 22 patients received local sustained release chemotherapy. The gliomas of 12 patients were totally resected, 8 were subtotally resected, and 2 were partially resected. Three BCNU-loaded biodegradable implants were implanted in 3 cases, 6 were implanted in 3 cases, 8 were implanted in 4 cases, 9 were implanted in 3 cases, 10 were implanted in 3 cases, and 12 were implanted in 6 cases. At day 28 after implantation, 11 patients did not have other treatment, 8 received the chemotherapeutic drugs based on nitrosoureas or temozolomide chemotherapy, and 3 received both radiotherapy and chemotherapy. The most common adverse reaction of the implants was subgaleal effusion (n=9). Other adverse reactions included rash (n=2), thrombocytopenia (n=1), and erythrocytopenia (n=1). The mean follow-up time was 55 months. Twenty of 22 patients died and 2 were still alive up to the last follow-up. The median survival time of the 22 patients was 322 d (95% CI 173-471 d). Conclusions The BCNU-loaded biodegradable implants are well tolerated and safe. The agents have a tendency of prolonging the survival time of patients with recurrent malignant glioma. It is worth conducting phase III clinical trial to evaluate the efficacy. Key words: Glioma; Neurosurgical procedures; Adjuvant chemotherapy

Post-bevacizumab Clinical Outcomes and the Impact of Early Discontinuation of Bevacizumab in Patients with Recurrent Malignant Glioma.

PurposeBevacizumab±irinotecan is effective for treatment of recurrent malignant gliomas. However, the optimal duration of treatment has not been established.Materials and MethodsNinety-four consecutive patients with recurrent malignant glioma who were treated with bevacizumab at our institutions were identified. Patients who continued bevacizumab until tumor progression were enrolled in a late discontinuation (LD) group, while those who stopped bevacizumab before tumor progression were enrolled in an early discontinuation (ED) group. Landmark analyses were performed at weeks 9, 18, and 26 for comparison of patient survival between the two groups.ResultsAmong 89 assessable patients, 62 (69.7%) and 27 (30.3%) patients were categorized as the LD and ED groups, respectively. According to landmark analysis, survival times from weeks 9, 18, and 26 were not significantly different between the two groups in the overall population. However, the LD group showed a trend toward increased survival compared to the ED group among responders. In the ED group, the median time from discontinuation to disease progression was 11.4 weeks, and none of the patients showed a definite rebound phenomenon. Similar median survival times after disease progression were observed between groups (14.4 weeks vs. 15.7 weeks, p=0.251). Of 83 patients, 38 (45.8%) received further therapy at progression, and those who received further therapy showed longer survival in both the LD and ED groups.ConclusionIn recurrent malignant glioma, duration of bevacizumab was not associated with survival time in the overall population. However, ED of bevacizumab in responding patients might be associated with decreased survival.

Abstract B3: Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan

Abstract BACKGROUND Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has demonstrated activity in the treatment of recurrent malignant glioma. High response rates have been observed, but particularly in WHO grade 3 gliomas, efforts to identify predictors of clinical response have been limited. Predictive markers and prognostic models are required in order to individualize treatment for this patient population. The primary endpoint of this study was to identify predictive biomarkers associated with response to bevacizumab therapy. The secondary endpoint was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). METHODS A total of 62 consecutive, recurrent grade 3 glioma patients were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. Baseline factors screened for potential prognostic and predictive value included: Age, gender, PS, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, MIB-1, MGMT, IDH1 and ATRX. Candidate factors with p-values below 5% were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modelling response and survival endpoints. RESULTS Twenty-two patients (35.5%) demonstrated a response according to the RANO criteria. Responders had significantly prolonged OS (p = 0.007) and trended toward longer PFS (p = 0.067) as compared to non-responders (OS: 12.4 vs 4.3 months, PFS: 5.6 vs 3.2 months). Presence of necrosis (OR: 0.17, CI: 0.04-0.68, p = 0.012) and a WHO performance status (PS) of more than 1 (OR: 0.04, CI: 0.002-0.89, p = 0.042) were more common in non-responders than responders. Female gender (HR: 0.48, CI: 0.28-0.82, p = 0.008) and a PS of 0-1 (HR: 0.20, CI: 0.10-0.41, p < 0.0001) were identified as positive prognostic factors for PFS. Immunohistochemical p53 negativity (HR: 0.47, CI: 0.26-0.87, p = 0.016) and low PS (HR: 0.17, CI: 0.07-0.39, p < 0.0001) correlated with extended OS and these factors were included in a prognostic model. CONCLUSIONS A favorable baseline PS and absence of necrosis were positively associated with response to bevacizumab treatment in recurrent grade 3 glioma patients. Low PS, female gender and p53 negativity are prognostic of improved outcome in this patient group. Citation Format: Anders Toft, Thomas Urup, Ib J. Christensen, Signe R. Michaelsen, Babloo S. Lukram, Kirsten Grunnet, Michael Kosteljanetz, Vibeke A. Larsen, Ulrik Lassen, Helle Broholm, Hans S. Poulsen. Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B3.

EPID-28PROGNOSTIC AND PREDICTIVE BIOMARKERS IN RECURRENT WHO GRADE 3 GLIOMA PATIENTS TREATED WITH BEVACIZUMAB AND IRINOTECAN

BACKGROUND: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A) has shown activity in the treatment of recurrent malignant glioma. Predictive markers and prognostic models are required in order to individualize treatment for grade 3 glioma patients. The primary endpoint of this study was to identify predictive biomarkers associated with response to bevacizumab therapy. The secondary endpoint was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). METHODS: A total of 62 consecutive, recurrent grade 3 glioma patients were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. A wide range of clinical, histopathological and molecular factors were screened for significant correlation (p < 0.05) with response and survival endpoints using logistic and Cox regression, respectively. Potentially predictive biomarkers were subjected to multivariate analysis. The landmark method was employed for analysis of survival by response. RESULTS: Twenty-two of 57 evaluable patients (38.6 %) demonstrated a response at the time of their best response MRI (RANO criteria). Responders had significantly prolonged OS (p = 0.007) and trended toward longer PFS (p = 0.067) as compared to non-responders (OS: 12.4 vs 4.3 months, PFS: 5.6 vs 3.2 months). A favorable WHO performance status (PS) and absence of necrosis were significantly more common in responders than non-responders. Multivariate analysis also identified a poor PS as the only prognostic factor for PFS, while an unfavorable PS and immunohistochemical p53 accumulation were prognostic of reduced OS. CONCLUSIONS: A poor baseline PS and the presence of necrosis were negatively associated with response to bevacizumab. An unfavorable PS and p53 positivity are prognostic of worse outcome in this patient population.

Multicenter Phase I Dose Escalation Study of Hypofractionated Stereotactic Radiotherapy with Bevacizumab in the Treatment of Recurrent Malignant Glioma (S43.005)

Multicenter Phase I Dose Escalation Study of Hypofractionated Stereotactic Radiotherapy with Bevacizumab in the Treatment of Recurrent Malignant Glioma (S43.005)

Retrospective analysis of safety and feasibility of a 3 days on/11 days off temozolomide dosing regimen in recurrent adult malignant gliomas.

We report the safety and feasibility of a 3 days on/11 days off temozolomide regimen for the treatment of recurrent malignant gliomas. Fifteen adult patients were treated; 14 were treated with 300 mg/m(2) and one treated with 250 mg/m(2). We reviewed the toxicity, progression-free survival (PFS), overall survival and objective response rate. Two patients (13%) experienced grade 3 nausea/vomiting and six patients (40%) experienced grade 3 lymphopenia. Dose reduction and treatment delay occurred in eight (53%) cases. One patient discontinued treatment due to uncontrolled nausea/vomiting. Median PFS for glioblastoma patients was 4.1 months and 6-month PFS was 25%. Twelve patients exhibited stable disease (86%), one patient (7%) had progressive disease and one patient (7%) showed a partial response. The '3 on/11 off' temozolomide regimen for recurrent high-grade gliomas was tolerable and warrants further study in a larger, prospective study.

Phase 1 Clinical Trial of Intratumoral Reovirus Infusion for the Treatment of Recurrent Malignant Gliomas in Adults

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 10(8) to 1 × 10(10) tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies.

Radiosurgery in the treatment of recurrent malignant gliomas: Experience at the Carlos Haya Hospital

Radiosurgery in the treatment of recurrent malignant gliomas: Experience at the Carlos Haya Hospital

Multicenter randomized controlled study of temozolomide versus semustine in the treatment of recurrent malignant glioma

To evaluate the efficacy and safety of temozolomide (TMZ) versus semustine (Me-CCNU) in the treatment of recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). A total of 151 patients with recurrent GBM or AA were enrolled into this randomized, multicentre and open-label study. And 144 patients (intent-to-treat (ITT) population) were assigned randomly into 2 groups. TMZ was given orally at 200 or 150 mg×m(-2)d(-1) (prior chemotherapy) for 5 days, repeated every 28 days. Me-CCNU was given orally at 150 mg×m(-2)×d(-1) once, repeated every 28 days. The treatment periods were within 2 - 6 months and the follow-up period was 6 months. Gadopentetate dimeglumine-magnetic resonance imaging (GD-MRI) or contrast-enhanced computed tomography was performed at 2, 3 and 6 months after treatment to evaluate the image-based progression. Progression-free survival (PFS), overall survival rates at the end of follow-up period and adverse events rates were evaluated. PFS at 6 months was 78.87% in TMZ group and 55.88% in Me-CCNU group (P < 0.05). Overall survival rates at the end of follow-up period were 96.89% in TMZ group and 97.30% in Me-CCNU group (P > 0.05). The objective response rate of TMZ and Me-CCNU groups were complete response (CR) (19.44% vs 6.38%), partial response (PR) (26.39% vs 14.89%), stable disease (SD) (26.39% vs 34.03%) and progressive disease (PD) (27.78% vs 44.68%, P < 0.01). Adverse events rates of TMZ and Me-CCNU were 29.11% and 45.15% respectively (P < 0.05). The efficacy of TMZ for patients with recurrent GBM or AA is better than that of Me-CCNU. And TMZ has an acceptable safety profile and its adverse events are mostly mild.

Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma

In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs). Eligible patients received daily temozolomide (50 mg/m2) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially "drugable" mutations in patients entering recurrent MG clinical trials. Among glioblastoma patients, median age was 56 y; median Karnofsky performance score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1). In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG. Clinical trials.gov identifier NCT00498927 (available at http://clinicaltrials.gov/ct2/show/NCT00498927).

Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas.

Abstract C4: Inhalational chemotherapy for malignant gliomas

Abstract Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer, based on its mechanism of action as a ras inhibitor and a cell cycle inhibitor. Unfortunately, it had significant gastrointestinal side effects, and was never well received as an oral anticancer agent. Recently, POH has been administered intranasally in a Phase I/II trial for the treatment of recurrent malignant gliomas in Brazil. It is well tolerated when delivered intranasally, with a 50% progression free survival (PFS) of 6 months in patients with recurrent GBM, with radiographic reduction in size in some patients. Similar efficacy compared to bevacizumab (Avastin; Genentech) was obtained in recurrent GBM patients treated with intranasal POH alone. We have recently synthesized a pharmaceutical grade of POH with &amp;gt;98% purity. Synthesized POH inhibits vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and transforming growth factor-beta 2 (TGF-B2). Cytotoxicity, as measured by colony formation assay (CFA), demonstrated a IC50 of 0.5 mM. We have since conjugated POH to a number of different pharmaceutical agents, including temozolomide (TMZ). Data on these conjugates demonstrate increased cytotoxic activity compared to individual drugs alone or in combination. TMZ-POH is much more potent than POH alone (IC50 10–30 uM), and is effective in TMZ resistant glioma cells, inhibits glioma cancer stem cells, and is not toxic to normal astrocytes. Our goal is to use our synthesized POH and TMZ-POH in upcoming Phase I/II trials for recurrent malignant gliomas. Further definition of the perillyl alcohol derivatives will lead to a pipeline of new compounds which will enable further expansion of the intranasal delivery repertoire. Animal models demonstrating efficacy of intranasal delivery of POH and TMZ-POH is currently underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C4.