Recurrent Malignant Glioma Research Articles

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.

Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study

ObjectiveThis surveillance study was conducted to verify the post-market safety and effectiveness of bevacizumab, which was approved in Japan in 2013 for the treatment of patients with newly diagnosed and or recurrent malignant glioma.MethodsThis was a prospective, observational, multicenter post-marketing surveillance study. Patients with newly diagnosed or recurrent malignant glioma scheduled for bevacizumab treatment were enrolled. The incidence and severity of adverse drug reactions were calculated. The effectiveness of bevacizumab was assessed by the 1-year survival rate and the overall survival rate.ResultsThe safety analysis set and the effectiveness analysis set each comprised 258 of the 268 enrolled patients: tumours were newly diagnosed in 80 patients (31%) and recurrent in 178 patients (68.9%). The incidence of grade ≥ 3 adverse drug reactions was 15.1%. Adverse drug reactions of special interest included 14 cerebral bleeding events and 11 infections. Of the 80 patients with newly diagnosed malignant glioma, 44 (55%) were alive throughout the 18-month observation period. The 1-year survival rate for patients with newly diagnosed glioblastoma was 78%. Median overall survival was not calculated, but 51.2% of patients were alive at the last date of observation of the last observed patient. In patients with recurrent glioblastoma, the 1-year survival rate was 38.9%, and the median overall survival was 10.2 months.ConclusionsThe results suggest no new safety concerns, and the effectiveness might be similar to previously reported data in clinical trials. Therefore, bevacizumab is considered as one of the treatment options for patients with malignant glioma in real-world clinical practice.

Synergistic Therapies for Recurrent Malignant Gliomas

Synergistic Therapies for Recurrent Malignant Gliomas

P14.08 Bevacizumab treatment for the lesion emerging after the radiotherapy for malignant glioma

Abstract BACKGROUND Because blocking vascular endothelial growth factor from reaching leaky capillaries is a logical strategy for the treatment, we reasoned that bevacizumab might be an effective treatment on recurrent malignant glioma and radiation necrosis (RN). In this study, the authors examined to differentiate RN from recurrent malignant glioma, and evaluated the results of bevacizumab treatment in each diagnosis. MATERIAL AND METHODS Four patients of malignant glioma (2 glioblastomas and 2 anaplastic astrocytomas), which demonstrated symptomatic lesion after radiotherapy, were involved in this study. All four patients were treated with bevacizumab on a 10 mg/kg biweekly (one cycle), for a total dose of 30 mg/kg (3 cycles) or furthermore. RN was differentiated from local recurrence in all four patients on the basis of 11C-methionine positron emission tomography and/or clinical course. Clinical evaluation and MRI studies were obtained after bevacizumab treatment in all cases repeatedly as possible. RESULTS Two patients were diagnosed as RN, and another two patients as tumor recurrence. Of the two patients with RN, neurological dysfunction was distinctly alleviated after bevacizumab treatment. Other two patients with tumor recurrence demonstrated no remarkable improvement in neurological dysfunction after bevacizumab treatment. Of all the two patients with RN, post-treatment MRI performed after the bevacizumab therapy showed a significant reduction of the massive lesion. CONCLUSION We concluded that bevacizumab could control the symptomatic massive lesion occurring after radiotherapy, and it might be more effective with the patients of RN, than with those of recurrent tumor.

P14.120 Phase II study of weekly carboplatin in pretreated adult malignant gliomas

Abstract BACKGROUND Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas MATERIAL AND METHODS This was a single arm, Phase II study. Eligibility criteria included progressive or recurrent malignant glioma after radiotherapy and chemotherapy-based treatments and Karnofsky Performance Status (KPS) > 60. RESULTS Thirty-two patients (median age: 43.5 y) were enrolled to receive weekly carboplatin monotherapy in intravenous mode of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival (PFS) was 2.3 months while overall survival (OS) was 5.5 months. Patients achieving clinical benefit exhibited a longer PFS (4.6 vs 1.5 months; p>0.001) and OS (7.9 vs 3.2 months; p=0.041) compared to those not achieving clinical benefit. CONCLUSION Our findings show that single agent, weekly, intravenous carboplatin may have a role in the treatment patients with recurrent malignant glioma

P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics

Abstract BACKGROUND Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors. MATERIAL AND METHODS Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed. RESULTS The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048). CONCLUSION Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.

OS6.5 ERGO2: A prospective randomized trial of a 9-day schedule of calorically restricted ketogenic diet and fasting or standard diet in addition to re-irradiation for malignant glioma

Abstract BACKGROUND Ketogenic diet (KD) and fasting have anticancer effects in tumor models, possibly due to a differential stress response with sensitization of tumor cells and protection of normal tissue. We therefore set up ERGO2 (NCT01754350), the first randomized clinical trial of calorically-restricted KD and intermittent fasting (KD-IF) in addition to re-irradiation for recurrent malignant gliomas. MATERIAL AND METHODS Patients were randomized 1:1 to re-irradiation combined with either calorically unrestricted diet (standard diet, SD) or KD-IF. The KD-IF schedule included 3 days of KD (21–23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary endpoints were PFS, local control, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life. RESULTS 50 patients were included. Four patients quit the trial before treatment and three patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6, and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of -2.1±1.8 kg. No severe adverse events attributable to the diet occurred. There was no difference in PFS6 between the two groups (KD-IF: 20%, SD: 16%). Similarly, no difference in PFS, local PFS6 and OS were observable. Explorative analysis revealed that among patients of the KD-IF group, those who achieved ketosis of at least 1.5 mmol/l had significantly longer PFS compared to those with lesser or no ketosis. CONCLUSION KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioblastoma. However, the short schedule reported here failed to increase the efficacy of re-irradiation.

Convection-Enhanced Delivery in Malignant Gliomas: A Review of Toxicity and Efficacy.

Malignant gliomas are undifferentiated or anaplastic gliomas. They remain incurable with a multitude of modalities, including surgery, radiation, chemotherapy, and alternating electric field therapy. Convection-enhanced delivery (CED) is a local treatment that can bypass the blood-brain barrier and increase the tumor uptake of therapeutic agents, while decreasing exposure to healthy tissues. Considering the multiple choices of drugs with different antitumor mechanisms, the supra-additive effect of concomitant radiation and chemotherapy, CED appears as a promising modality for the treatment of brain tumors. In this review, the CED-related toxicities are summarized and classified into immediate, early, and late side effects based on the time of onset, and local and systemic toxicities based on the location of toxicity. The efficacies of CED of various therapeutic agents including targeted antitumor agents, chemotherapeutic agents, radioisotopes, and immunomodulators are covered. The phase III trial PRECISE compares CED of IL13-PE38QQR, an interleukin-13 conjugated to Pseudomonas aeruginosa exotoxin A, to Gliadel® Wafer, a polymer loaded with carmustine. However, in this case, CED had no significant median survival improvement (11.3 months vs. 10 months) in patients with recurrent glioblastomas. In phase II studies, CED of recombinant poliovirus (PVSRIPO) had an overall survival of 21% vs. 14% for the control group at 24 months, and 21% vs. 4% at 36 months. CED of Tf-diphtheria toxin had a response rate of 35% in recurrent malignant gliomas patients. On the other hand, the TGF-β2 inhibitor Trabedersen, HSV-1-tk ganciclovir, and radioisotope 131I-chTNT-1/B mAb had a limited response rate. With this treatment, patients who received CED of the chemotherapeutic agent paclitaxel and immunomodulator, oligodeoxynucleotides containing CpG motifs (CpG-ODN), experienced intolerable toxicity. Toward the end of this article, an ideal CED treatment procedure is proposed and the methods for quality assurance of the CED procedure are discussed.

A Second Course of Radiotherapy in Patients with Recurrent Malignant Gliomas: Clinical Data on Re-irradiation, Prognostic Factors, and Usefulness of Digital Biomarkers.

The treatment of malignant gliomas has undergone a significant intensification during the past decade, and the interdisciplinary treatment team has learned that all treatment opportunities, including surgery and radiotherapy (RT), also have a central role in recurrent gliomas. Throughout the decades, re-irradiation (re-RT) has achieved a prominent place in the treatment of recurrent gliomas. A solid body of evidence supports the safety and efficacy of re-RT, especially when modern techniques are used, and justifies the early use of this regimen, especially in the case when macroscopic disease is present. Additionally, a second adjuvant re-RT to the resection cavity is currently being investigated by several investigators and seems to offer promising results. Although advanced RT technologies, such as stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) have become available in many centers, re-RT should continue to be kept in experienced hands so that they can select the optimal regimen, the ideal treatment volume, and the appropriate techniques from their tool-boxes. Concomitant or adjuvant use of systemic treatment options should also strongly be taken into consideration, especially because temozolomide (TMZ), cyclohexyl-nitroso-urea (CCNU), and bevacizumab have shown a good safety profile; they should be considered, if available. Nonetheless, the selection of patients for re-RT remains crucial. Single factors, such as patient age or the progression-free interval (PFI), fall too short. Therefore, powerful prognostic scores have been generated and validated, and these scores should be used for patient selection and counseling.

Bevacizumab reduces toxicity of reirradiation in recurrent high-grade glioma

PurposeThe role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences. Patients and methodsAll adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan–Meier method. Prognostic factors were obtained from proportional hazards models. ResultsBEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026). ConclusionConcomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols.

Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era.

Boron neutron capture therapy (BNCT) has a unique property of tumor-cell-selective heavy-particle irradiation. BNCT can form large dose gradients between cancer cells and normal cells, even if the two types of cells are mingled at the tumor margin. This property makes it possible for BNCT to be used for pre-irradiated locally recurrent tumors. Shallow-seated, locally recurrent lesions have been treated with BNCT because of the poor penetration of neutrons in the human body. BNCT has been used in clinical studies for recurrent malignant gliomas and head and neck cancers using neutron beams derived from research reactors, although further investigation is warranted because of the small number of patients. In the latter part of this review, the development of accelerator-based neutron sources is described. BNCT for common cancers will become available at medical institutes that are equipped with an accelerator-based BNCT system. Multiple metastatic lung tumors have been investigated as one of the new treatment candidates because BNCT can deliver curative doses of radiation to the tumors while sparing normal lung tissue. Further basic and clinical studies are needed to move toward an era of accelerator-based BNCT when more patients suffering from refractory cancers will be treated.

Combination of PVSRIPO and Atezolizumab for Adults With Recurrent Malignant Glioma

Combination of PVSRIPO and Atezolizumab for Adults With 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.

Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

Randomized Prospective Trial of Stereotactic Radiosurgery versus Chemotherapy for Recurrent Malignant Glioma after Second-line Chemotherapy (S14.005)

Randomized Prospective Trial of Stereotactic Radiosurgery versus Chemotherapy for Recurrent Malignant Glioma after Second-line Chemotherapy (S14.005)

OA40 - Randomized Prospective Trial of Stereotactic Radiosurgery versus Chemotherapy for Recurrent Malignant Glioma After Second-line Chemotherapy

OA40 - Randomized Prospective Trial of Stereotactic Radiosurgery versus Chemotherapy for Recurrent Malignant Glioma After Second-line Chemotherapy

Возможности протонной терапии при повторном облучении рецидивных глиом

Purpose: To define efficiency and safety of use of the active scanning proton beam in reirradiation of recurrent malignant gliomas. Material and methods: Researched group included 26 patients who were treated on a complex of proton therapy Prometeus. 57.7 % of tumors were glioblastoma, 26.9 % – gliomas of GII and 15.4 % GIII gliomas. Proton therapy was carried out with use of the active scanning beam, image-guiding system and use of the individual fixing devices. To all patients PET/CT with 11C-methionine and MRI were carried out, target volume delineation was carried out by results of coregistration of both images. Results: Terms of observation were from 1 to 32 months. The assessment of direct efficiency is carried out at 19 patients in 3 months after completion of treatment. From the group 52.7 % of patients (n = 10) had disease stabilization. At 11.5 % (n = 3) – partial response. Tumor regression volume varied from 50 to 90 %. Progressing of a disease developed in 31.5 % of the considered cases (n = 6). Other 7 patients expect control inspection. 15.4 % (n = 4) patients developed grade 2 radiodermatitis in the field of radiation fields, the remaining 84.6 % (n = 22) had grade 1 radiodermatitis. Of the entire group of patients, only one case of the development of a late radiation complication in the form of radionecrosis is observed at an observation period of 13 months. Conclusion: Preliminary results of a research showed that performing proton therapy by the active scanning beam is the effective method of treatment of patients with the diagnosed recurrent gliomas, allowing to increase life expectancy of patients with maintaining satisfactory general condition.

Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma

ABSTRACTIntroduction: Glioblastoma and anaplastic astrocytoma are two of the most aggressive and common glioma malignancies in adults. These high-grade gliomas (HGG) universally recur despite aggressive treatment modalities and have a median overall survival (mOS) of approximately 14 months from initial diagnosis. Upon recurrence, there is no standard of care and these patients have a dismal prognosis of around 9 months at time of recurrence.Areas covered: In this article, we assess the newly published phase I data of Toca 511 and Toca FC, a two-drug combination therapy for recurrent HGG (rHGG) tumors, for effectiveness and safety.Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. Furthermore, all responders were complete responses after extended follow-up. The drug is well tolerated for most patients. Responders tended to be young and have high-performance scores prior to beginning therapy, but more studies are necessary to understand the patient profile that receives the most benefit. Randomized-controlled trials are warranted for Toca 511 and Toca FC to confirm drug efficacy.

Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy.

To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation.Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis. Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff. APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity.

Salvage Leksell Stereotactic Radiosurgery for Malignant Gliomas.

The outcome of patients with malignant gliomas has not substantially improved, even with advances in imaging, neurosurgery, molecular subtyping, and radiation, and newer oncologic options. Maximal safe resection when feasible remains the initial treatment of choice for most malignant gliomas. These tumors often recur and require additional therapy to control the tumor growth. Leksell stereotactic radiosurgery (SRS) is offered as salvage therapy in patients with recurrent or residual malignant gliomas. SRS is well tolerated and is associated with a relatively low risk of adverse radiation effects in malignant glial tumor patients who otherwise have relatively few options. SRS allows the surgeon more flexibility in terms of surgical options and may enhance quality of life for patients postoperatively. Although randomized controlled studies are lacking in the use of salvage SRS after the failure of initial standard of care management, preliminary data suggest that radiosurgery improves tumor control and overall survival for patients with recurrent malignant gliomas.