Treatment Of High-grade Gliomas Research Articles

Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives

Resistance mechanisms employed by high-grade gliomas allow them to successfully evade current standard treatment of chemotherapy and radiation treatment. Withaferin A (WA), utilized in Ayurvedic medicine for centuries, is attracting attention for its antitumor capabilities. Here we review pertinent literature on WA as a high-grade glioma treatment, and discuss the cancerous mechanisms it affects. WA is relatively nontoxic and has shown potential in crossing the blood-brain barrier. WA prevents p53 alterations and inactivates overexpressed MDM2 through ARF and ROS production. Furthermore, WA upregulates Bax, inducing mitochondrial death cascades, inhibits mutated Akt, mTOR, and NF-κB pathways, and inhibits angiogenesis in tumors. Therapy with WA for high-grade gliomas is supported through the literature. Further investigation is warranted and encouraged to fully unearth its abilities against malignant gliomas.

Targeting and killing glioblastoma with monoclonal antibody to O-acetyl GD2 ganglioside.

There are still unmet medical needs in the treatment of glioblastoma, the most common and the most aggressive glioma of all brain tumors. Here, we found that O-acetyl GD2 is expressed in surgically resected human glioblastoma tissue. In addition, we demonstrated that 8B6 monoclonal antibody specific for O-acetylat GD2 could effectively inhibit glioblastoma cell proliferation in vitro and in vivo. Taken together, these results indicate that O-acetylated GD2 represents a novel antigen for immunotherapeutic-based treatment of high-grade gliomas.

Validation of a semi-automatic co-registration of MRI scans in patients with brain tumors during treatment follow-up

There is an expanding research interest in high-grade gliomas because of their significant population burden and poor survival despite the extensive standard multimodal treatment. One of the obstacles is the lack of individualized monitoring of tumor characteristics and treatment response before, during and after treatment. We have developed a two-stage semi-automatic method to co-register MRI scans at different time points before and after surgical and adjuvant treatment of high-grade gliomas. This two-stage co-registration includes a linear co-registration of the semi-automatically derived mask of the preoperative contrast-enhancing area or postoperative resection cavity, brain contour and ventricles between different time points. The resulting transformation matrix was then applied in a non-linear manner to co-register conventional contrast-enhanced T1 -weighted images. Targeted registration errors were calculated and compared with linear and non-linear co-registered images. Targeted registration errors were smaller for the semi-automatic non-linear co-registration compared with both the non-linear and linear co-registered images. This was further visualized using a three-dimensional structural similarity method. The semi-automatic non-linear co-registration allowed for optimal correction of the variable brain shift at different time points as evaluated by the minimal targeted registration error. This proposed method allows for the accurate evaluation of the treatment response, essential for the growing research area of brain tumor imaging and treatment response evaluation in large sets of patients. Copyright © 2016 John Wiley & Sons, Ltd.

Nonclinical Safety and Toxicokinetics of MnTnBuOE-2-PyP5+ (BMX-001).

BMX-001, a manganese porphyrin that has anti-inflammatory, antioxidant, and antitumor properties, is being developed as a potential therapeutic for high-grade glioma (HGG) and head and neck (H&N) cancer. An IND has been opened for BMX-001 in the treatment of HGG (NCT02655601) and another is in preparation for H&N. The safety of BMX-001 has been evaluated in a battery of nonclinical Good Laboratory Practice (GLP)-compliant studies. Systemic toxicity has been evaluated using the intended cGMP product administered subcutaneously for periods of up to 5 weeks in both the mouse and the monkey and included toxicokinetic evaluations to characterize systemic exposure and tissue distribution and clearance of BMX-001. In additional GLP studies, BMX-001 was not irritating to the skin or eye and caused no changes in cardiac rate or rhythm or blood pressure. Mixed results for genotoxicity were seen with the weight of evidence indicating that BMX-001 poses no genotoxic risk in humans. In systemic mouse and monkey studies, loading/maintenance dose no observed adverse effect levels were 12/2 mg/kg/dose and 6/2 mg/kg/dose, respectively, with maintenance doses administered every 3 days after the initial loading dose. Systemic data were used to determine a Food and Drug Administration-approved safe starting dose for the initial clinical study in patients with HGG. BMX-001 was detected in analyzed tissues, including the brain, persisting well past the short plasma clearance period. The highest levels of BMX-001 were seen in the liver and kidneys, with amounts in these tissues returning to close to undetectable levels after a 2-week cessation of dosing.

Hippocampal Sparing Post-Operative Radiation Therapy and Its Impact on Memory Function in Newly Diagnosed High Grade Glioma Patients

Background: Gliomas are the most common primary brain tumors. The combination of surgery, post-operative radiotherapy with concurrent and adjuvant chemotherapy represents the standard approach to the treatment of high grade gliomas. Three-dimensional conformal therapy (3DCRT) is increasingly used in the treatment of primary brain tumours. The use of intensity-modulated radiotherapy (IMRT) yields conformal dose distributions and better avoidance of organs at risk. Memory impairment is a well-documented side effect of cranial irradiation. One possible hypothesis focuses on a neurogenic stem cell compartment in the hippocampus that is highly sensitive to radiation and potentially central to radiation-induced memory impairment. Objectives: In this study we evaluated the possibility of sparing the hippocampi in post-operative radiation therapy for high grade glioma (3DCRT/IMRT technique) and its impact on preservation of memory function. Methods: A total of 20 newly diagnosed, histologically confirmed cases of high grade glioma fulfilling the eligibility criteria were enrolled into the study. Patients received post-operative radiation therapy with concurrent and adjuvant temozolomide via the 3DCRT (3DCRT arm) / IMRT (IMRT arm) technique. Evaluation of dose to hippocampi (ipsilateral and contralateral) was done along with serial evaluation of memory function. Two groups were compared for the dose received by hippocampi and its impact on memory function. Results: Bilateral hippocampal sparing was achieved in all patients in IMRT arm. Whereas, in 3DCRT arm ipsilateral, hippocampus could be spared in 60% of patients. Memory function analysis showed that patients in IMRT arm had maintenance of the score for a period of 3 months post radiotherapy, while patients in 3DCRT arm showed a decline immediately after radiotherapy. Conclusions: Bilateral hippocampal sparing with preservation of memory function is achievable with IMRT technique for delivery of post-operative radiotherapy in patients with high grade glioma without compromise in prescribed dose delivery.

The value of using a brain laser interstitial thermal therapy (LITT) system in patients presenting with high grade gliomas where maximal safe resection may not be feasible.

BackgroundThe objective of this analysis was to determine the value (incremental cost/increment benefit) of a brain LITT system versus employing current surgical options recommended by NCCN guidelines, specifically open resection (i.e. craniotomy) methods or biopsy (collectively termed CURRENT TREATMENTS) in patients where maximal safe resection may not be feasible. As has been demonstrated in the literature, extent of resection/ablation with minimal complications are independently related to overall survival.MethodsA cost effectiveness analysis from a societal perspective was employed using TreeAge Pro 2014 software. Direct costs (using national average Medicare reimbursement amounts), outcomes (overall survival), and value [defined as increment cost/incremental survival—evaluated as cost/life year gained (LYG)] were evaluated. Sensitivity analysis was also performed to determine which variables had the largest effect on incremental costs and outcomes.ResultsIn the base case, the overall survival was improved with brain LITT versus CURRENT TREATMENTS by 3.07 months at an additional cost of $7508 (or $29,340/LYG). This amount was significantly less than the current international threshold value for $32,575/LYG and considerably less than the US threshold value of $50,000/LYG. This incremental cost may also qualify under NICE criteria for end of life therapies. In sensitivity analysis: As percent local recurrence GBM increased; cost of DRG25/26 increased; percent GTR increased; and gliadel use increased—the value of brain LITT improved. Additionally, in those patients where a biopsy is the only option, brain LITT extended life by 7 months.ConclusionsBrain LITT should be considered a viable option for treatment of high grade gliomas as it improves survival at a cost which appears to be of good value to society. This incremental cost is less than the international and US thresholds for good value.

Evaluation of helical tomotherapy in the treatment of high-grade gliomas near critical structures.

Our purpose was to investigate the role of helical tomotherapy using a simultaneous integrated boost technique for the treatment of high-grade gliomas near intracranial critical structures. Of 27 patients treated with helical tomotherapy, 11 were eligible. Only patients whose tumors were within 0.5 cm of the optic chiasm, the optic nerve or the brainstem were included. The therapeutic approach was a simultaneous integrated boost, prescribing 66 and 60 Gy to the PTV1 and PTV2, respectively, in 30 fractions. All patients received concomitant temozolomide at a dose of 75 mg/m2 daily during radiation therapy. Of the 11 patients considered, 3 patients (27%) died after 4 months from the completion of the combined treatment. Three patients (27%) presented local progression, and the median time to disease progression was 6 months (range, 1-12). Five patients (45%), at the time of this evaluation, did not have signs or symptoms of recurrence or progression of the disease. Acute toxicity, evaluated during radiochemotherapy, was minimal, with all patients experiencing RTOG grade 0 and grade 1 toxicity. . Helical tomotherapy proved to be an effective and safe treatment modality, with an improvement of accuracy in delivery of high-dose radiotherapy despite the presence of nearby critical structures.

Nitrosoureas in the Management of Malignant Gliomas

Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas.

ATPS-16IDENTIFICATION OF CLINICALLY RELEVANT DRUGS FOR GLIOBLASTOMA WITH SPECIFIC MOLECULAR SIGNATURE USING CHEMICAL BIOLOGY FINGERPRINTING

Translating molecular subtyping of glioblastoma (GBM) into therapeutically actionable guidance remains an unfulfilled opportunity. A central challenge is to discover therapeutic targets matched to agents (drugs or tool compounds) that are predictably present in subclasses of GBM. Transcriptional patterns in GBM cases in TCGA can identify 12 distinct molecular contexts (mC), where, across a subset of genes and tumors, conditional dependencies of gene expression (signal & echo relationships) consistently emerge. We deployed a panel of 64 patient-derived xenografts from GBM patients whose gene expression profiles allow mapping against the same 12 molecular contexts identified from TCGA cases. These clinically-relevant, preclinical models afford bioinformatics mining for actionable targets as well as chemical library screening for activity against short-term cultures derived from the PDX models. Utilizing a technique we term Chemical Biology Fingerprinting (CBF), we interrogated a series of GBM PDX models using a small chemical library (650 compounds) of clinically relevant anti-cancer agents to uncover context-specific chemovulnerabilities. Preliminary data demonstrated that, mC14 GBM (GBM59, SF7300, GBM116), characterized by mt-P53 and transcriptional similarity to GBM proneural subtype, show distinct vulnerability to Arsenic Trioxide (ATO) as compared to mC4 GBM (GBM91, GBM102), characterized by CHEK2 and NF1 mutations and transcriptional patterns similar to GBM mesenchymal subtype. To clinically-validate an ATO vulnerability signature, we acquired 22 treatment naive archival patient samples, who were part of Phase I/II clinical trial to study efficacy of ATO and Temozolomide (TMZ) in combination with radiation in treatment of high grade gliomas (NCT00275067) and which exhibited varied survival with ATO treatment (91 days to >1000 days), and determined their molecular context classification using whole transcriptome sequencing (RNAseq). In summary, we demonstrate a subclassification of GBM into novel contexts and we also show that these contexts are differentially sensitive to clinically relevant drugs. Supported by NIH U01CA168397.

HCP-01DIAGNOSIS AND MANAGEMENT OF HIGH-GRADE GLIOMA IN PATIENTS WITH HIV

BACKGROUND: While opportunistic infections and lymphoma are common causes of a brain mass in immunosuppressed patients with HIV, primary brain tumor is more likely in those with CD4 counts > 500 cells/mm3. Small series have noted a higher than expected frequency of high-grade glioma (HGG) in HIV patients, but they remain rare with fewer than 40 cases reported. This study adds 4 from an inner city population. METHODS: Retrospective case series. Chart review. RESULTS: Four patients were identified – 3 women with GBM and 1 man with anaplastic astrocytoma (AA). Median age at tumor diagnosis was 57.5 (range 48-66). All patients were on HAART at time of diagnosis and median CD4 count was 516 cells/mm3 (range 359-888 cells/mm3). For 3 patients with available data, median time between HIV and HGG diagnoses was 5 years (range 2-8). Median time from presentation to HGG diagnosis was 34 days (range 9-59). At presentation, HGG was considered the most likely diagnosis for all GBM patients; differential for the AA patient included low-grade glioma, infectious or inflammatory process. Three patients underwent CSF sampling to investigate alternate diagnoses. Empiric toxoplasmosis therapy was initiated in 1, but stopped after 4 days. All patients underwent subtotal resection followed by chemo-radiation with temozolomide (TMZ). No patient required dose reduction for hematological toxicity. One experienced a drop in CD4 count to 29 cells/mm3 despite undetectable viral load. Two patients received therapy at recurrence; agents included bevacizumab and irinotecan. Three died (OS range 4-17 months); 1 remains alive 22 months from diagnosis. CONCLUSIONS: HGG should be a strong diagnostic consideration in immune-competent HIV patients presenting with brain mass. Additional testing for toxoplasmosis and lymphoma is low-yield and should not delay surgical diagnosis. Treatment for HGG in such patients should be the same as the general population.

ATPS-27SIMULTANEOUS TARGETING OF THE CELL CYCLE AND GLOBAL TRANSCRIPTION BY IRREVERSIBLE INHIBITION OF CDK7 AS A NOVEL THERAPEUTIC APPROACH FOR HIGH-GRADE GLIOMA

High-grade glioma (HGG) is an aggressive brain neoplasm that is incurable. Targeted therapies are promising replacements or adjuncts to traditional therapies but have so far been unsuccessful. One problem is that HGG is characterised by a diverse range of genetic aberrations, including in the receptor tyrosine kinase (RTK) signalling and cell cycle regulation pathways, which drive tumor proliferation and survival. Another is that HGG has a highly heterogeneous intratumoral transcriptional profile allowing adaptation to a range of therapeutics. Cyclin dependent kinase 7 (CDK7) presents an opportunity to simultaneously target proliferation to prevent tumor growth and global transcription to prevent transcriptional adaptation to therapy, as this enzyme forms the CDK activating kinase that controls progression through multiple checkpoints in the cell cycle and also stabilises the RNA polymerase II-based transcriptional apparatus needed for efficient gene transcription. Using a new and irreversible inhibitor of CDK7, THZ1, we demonstrate that a panel of 10 patient-derived primary gliomaspheres, representing a diverse range of genotypes and phenotypes, were all highly sensitive to THZ1 treatment, with IC50 values of <100 nM. THZ1 induced global transcription downregulation, as determined by microarray analysis, and resulted in potent caspase 3/7 activation and apoptosis. In all gliomaspheres, the cell cycle was arrested at the G2/M phase regardless of TP53, CDKN2A/B or RB status, with substantial aneuploidy observed, a trait linked to the decreased stability of the anti-apoptotic protein survivin. THZ1 treatment resulted in a loss of total and cell surface expression of several RTKs critical to driving gliomagenesis, including EGFR, EGFRvIII, PDGFR-α, PDGFR-β, MET, FGFR3 and AXL. This resulted in a marked reduction in PI3K/AKT, MAPK/ERK and STAT3 activation, regardless of PTEN, PI3K or RAS status. In vivo orthograft experiments will also be presented. These findings suggest that irreversible inhibition of CDK7 is a novel and effective treatment for HGG.

Patterns of Salvage Treatment for High Grade Glioma in Patients Who Received Upfront Temozolomide

Patterns of Salvage Treatment for High Grade Glioma in Patients Who Received Upfront Temozolomide

The use of 18F-FDG PET to differentiate progressive disease from treatment induced necrosis in high grade glioma

In the follow-up of patients treated for high grade glioma, differentiation between progressive disease (PD) and treatment-induced necrosis (TIN) is challenging. The purpose of this study is to evaluate the diagnostic accuracy of FDG PET for the differentiation between TIN and PD after high grade glioma treatment. We retrospectively identified patients between January 2011 and July 2013 that met the following criteria: age >18; glioma grade 3 or 4; treatment with radiotherapy or chemoradiotherapy; new or progressive enhancement on post treatment MRI; FDG PET within 4 weeks of MRI. Absolute and relative (to contralateral white matter) values of SUVmax and SUVpeak were determined in new enhancing lesions on MRI. The outcome of PD or TIN was determined by neurosurgical biopsy/resection, follow-up MRI, or clinical deterioration. The association between FDG PET and outcome was analyzed with univariate logistic regression and ROC analysis for: all lesions, lesions >10, >15, and >20 mm. We included 30 patients (5 grade 3 and 25 grade 4), with 39 enhancing lesions on MRI. Twenty-nine lesions represented PD and 10 TIN. Absolute and relative values of SUVmax and SUVpeak showed no significant differences between PD and TIN. ROC analysis showed highest AUCs for relative SUVpeak in all lesion sizes. Relative SUVpeak for lesions >20 mm showed reasonable discriminative properties [AUC 0.69 (0.41–0.96)]. FDG PET has reasonable discriminative properties for differentiation of PD from TIN in high grade gliomas larger than 20 mm. Overall diagnostic performance is insufficient to guide clinical decision-making.

Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma.

Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

Secondary Solid Malignancies After High-Grade Glioma Treatment in Pediatric Patients

Due to the poor survival in high-grade glioma (HGG), secondary solid malignancies (SSM) following pediatric HGG are scarce. The authors present the experience from the HIT-HGG database in Germany, Austria, and Switzerland. Five out of 1228 pediatric HGG patients developed a SSM following a latency of 29–122 months from primary HGG diagnosis. In 4 patients, the SSM may be attributed to previous radiotherapy or a tumor predisposition syndrome, reflected by a markedly increased cumulative incidence rate of SSM in patients with tumor predisposition. Survival was devastating, since none of the patients survived beyond 18 months from SSM diagnosis.

Standardized MRI assessment of high-grade glioma response: a review of the essential elements and pitfalls of the RANO criteria.

Accurately evaluating response in the treatment of high-grade gliomas presents considerable challenges. This review looks at the advancements made in response criteria while critically outlining remaining weaknesses, and directs our vision toward promising endpoints to come. The 2010 guidelines from the Response Assessment in Neuro-Oncology (RANO) working group have enhanced interpretation of clinical trials involving novel treatments for high-grade glioma. Yet, while the criteria are considered clinically applicable to high-grade glioma trials, as well as reasonably accurate and reproducible, RANO lacks sufficient detail for consistent implementation in certain aspects and leaves some issues from the original Macdonald guidelines unresolved. To provide the most accurate assessment of response to therapeutic intervention currently possible, it is essential that trial oncologists and radiologists not only have a solid understanding of RANO guidelines, but also proper insight into the inherent limitations of the criteria. With the expectation of improved data collection as a standard, the author anticipates that the next high-grade glioma response criteria updates will incorporate advanced MRI methods and quantitative tumor volume measurements, availing a more accurate interpretation of response in the future.

The role of Gliadel wafers in the treatment of newly diagnosed GBM: a meta-analysis.

BackgroundStandard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as a treatment for malignant glioma is currently a controversial topic among neurosurgeons. Our meta-analysis focused on whether carmustine wafer treatment could significantly benefit the survival of patients with newly diagnosed glioblastoma multiforme (GBM).MethodWe searched the PubMed and Web of Science databases without any restrictions on language using the keywords “Gliadel wafers”, “carmustine wafers”, “BCNU wafers”, or “interstitial chemotherapy” in newly diagnosed GBM for the period from January 1990 to March 2015. Randomized controlled trials (RCTs) and cohort studies/clinical trials that compared treatments designed with and without carmustine wafers and which reported overall survival or hazard ratio (HR) or survival curves were included in this study. Moreover, the statistical analysis was conducted by the STATA 12.0 software.ResultsSix studies including two RCTs and four cohort studies, enrolling a total of 513 patients (223 with and 290 without carmustine wafers), matched the selection criteria. Carmustine wafers showed a strong advantage when pooling all the included studies (HR =0.63, 95% confidence interval (CI) =0.49–0.81; P=0.019). However, the two RCTs did not show a statistical increase in survival in the group with carmustine wafer compared to the group without it (HR =0.51, 95% CI =0.18–1.41; P=0.426), while the cohort studies demonstrated a significant survival increase (HR =0.59, 95% CI =0.44–0.79; P<0.0001).ConclusionCarmustine-impregnated wafers play a significant role in improving survival when used for patients with newly diagnosed GBM. More studies should be designed for newly diagnosed GBM in the future.

Profile of nimotuzumab in the treatment of high-grade glioma.

High-grade gliomas (HGG) are extremely aggressive lesions and represent the most common primary malignant brain tumors without an effective therapy. Standard treatment for HGG usually includes surgery followed by radiotherapy and chemotherapy. However, the prognosis of patients with HGG remains dismal. We review the humanized epidermal growth factor receptor (EGFR) and the major EGFR target drugs in HGG treatments, focusing on the EGFR antibody nimotuzumab as a new therapeutic strategy in HGG. We found that nimotuzumab with or without radiotherapy, chemotherapy in newly diagnosed or recurrent HGG, such as glioblastoma multiforme (GBM), anaplastic astrocytomas (AA), and diffuse intrinsic pontine glioma (DIPG), might improve the response rate or the survival time. In conclusion, nimotuzumab is a very well-tolerated drug with acceptable toxicity, and it may have promising value in the combination treatment. As a result, multiple center randomized controlled Phase III clinical trials need to be conducted to confirm the efficacy and toxicity for nimotuzumab in HGG.

Polymeric drug delivery for the treatment of glioblastoma.

Glioblastoma (GBM) remains an almost universally fatal diagnosis. The current therapeutic mainstay consists of maximal safe surgical resection followed by radiation therapy (RT) with concomitant temozolomide (TMZ), followed by monthly TMZ (the "Stupp regimen"). Several chemotherapeutic agents have been shown to have modest efficacy in the treatment of high-grade glioma (HGG), but blood-brain barrier impermeability remains a major delivery obstacle. Polymeric drug-delivery systems, developed to allow controlled local release of biologically active substances for a variety of conditions, can achieve high local concentrations of active agents while limiting systemic toxicities. Polymerically delivered carmustine (BCNU) wafers, placed on the surface of the tumor-resection cavity, can potentially provide immediate chemotherapy to residual tumor cells during the standard delay between surgery and chemoradiotherapy. BCNU wafer implantation as monochemotherapy (with RT) in newly diagnosed HGG has been investigated in 2 phase III studies that reported significant increases in median overall survival. A number of studies have investigated the tumoricidal synergies of combination chemotherapy with BCNU wafers in newly diagnosed or recurrent HGG, and a primary research focus has been the integration of BCNU wafers into multimodality therapy with the standard Stupp regimen. Overall, the results of these studies have been encouraging in terms of safety and efficacy. However, the data must be qualified by the nature of the studies conducted. Currently, there are no phase III studies of BCNU wafers with the standard Stupp regimen. We review the rationale, biochemistry, pharmacokinetics, and research history (including toxicity profile) of this modality.

Prolonged treatment with bevacizumab is associated with brain atrophy: a pilot study in patients with high-grade gliomas.

Bevacizumab is widely used for treatment of high-grade gliomas and other malignancies. Because bevacizumab has been shown to be associated with neurocognitive decline, this study is designed to investigate whether prolonged treatment with bevacizumab is also associated with brain atrophy. We identified 12 high-grade glioma patients who received bevacizumab for 12 months at the first recurrence and 13 matched controls and blindly compared the volumes of the contralateral hemispheres and contralateral ventricle in these two groups at baseline and after 12 ± 2 months of the baseline scan by two independent analyses. The volumes of the contralateral hemispheres and ventricles did not differ significantly between the two groups at baseline. Whereas, in the control group the volumes of the contralateral hemisphere changed subtly from baseline to follow-up (p = 0.23), in the bevacizumab-treated group the volumes significantly decreased from baseline to follow-up (p = 0.03). There was significant increase in the contralateral ventricle volume from base line to follow-up scans in both the control group (p = 0.01) and in the bevacizumab group (p = 0.005). Both the absolute and the percentage changes of contralateral hemisphere volumes and contralateral ventricular volumes between the two patient groups were statistically significant (p < 0.05). Results of this study demonstrate prolonged treatment with bevacizumab is associated with atrophy of the contralateral brain hemisphere.