Management Of Glioblastoma Multiforme Research Articles

P05 * VARIABILITY IN FOLLOW UP IMAGING GUIDELINES AFTER THE COMPLETION OF PRIMARY THERAPY IN GLIOBLASTOMA MULTIFORME

INTRODUCTION: There is no clear definitive follow up surveillance imaging guideline after the completion of primary therapy in glioblastoma multiforme (GBM). Here we provide the first report analysing international, national and local guidelines in GBM imaging surveillance. METHOD: We performed a systematic review of GBM management guidelines indexed in PUBMED and EMBASE databases up until October 2013. We also searched for GBM guidelines on websites of relevant international and national societies. To clarify local recommendations within the UK, we reviewed all guideline documents produced by local neuro-oncology multidisciplinary teams (MDTs; n = 28) in the UK accessed via the Care Quality Improvement Network (CQuIN) database. For all the relevant guidelines identified, we extracted imaging recommendations for the period following completion of primary therapy. RESULTS: Out of the identified guidelines produced by international and national societies, only 6 had follow up imaging guidelines with variability in imaging frequency ranging from 1-2 monthly (1 guideline), 2-4 monthly (1), 2-3 monthly (2), to 3-4 monthly (2). Twenty out of the 28 neuro-oncology MDTs had imaging guidelines. Of these, 18 had guidelines on imaging after completion of primary therapy, with also a wide variability in imaging frequency from 2 monthly (2 guidelines), 2-4 monthly (1), 3 monthly (6), 3-4 monthly (1), 3-6 monthly (2), 6 monthly (4), and yearly (2). CONCLUSION: The guidelines for follow up imaging surveillance after the completion of primary therapy in GBM are variable. Future studies should assess effectiveness of these guidelines in detecting assymptomatic GBM recurrence.

P17.34 * CONCURRENT CHEMORADIOTHERAPY IN GLIOBLASTOMA MULTIFORME: RETROSPECTIVE STUDY

BACKGROUND: Concurrent radiotherapy with Temozolomide (TMZ) is the standard of care in management of Glioblastoma Multiforme (GBM) since it led to survival benefit over radiotherapy alone. On the basis of this evidence, we initiated this study. The aim of this work was to investigate the efficacy and tolerability of radiotherapy plus TMZ in the treatment for newly diagnosed patients with GBM. METHODOLOGY: This is a retrospective descriptive study including newly diagnosed patients with GBM in clinical oncology department at Ain Shams University Hospitals during the period from January 2010 till December 2012. Eligible patients were treated with radiotherapy to a total dose of 60Gy/ 30 fractions/ 6 weeks concurrently with TMZ 75mg/m2 daily during the course of radiation followed by TMZ as adjuvant treatment for up to 6 cycles. RESULTS: During the period from January 2010 till December 2012, 57 GBM patients were enrolled in this retrospective study. The majority of the study group were males and constituted 77.2% (n = 44) while females constituted 22.8% (n = 13). The mean age was 52.2 years +/-10.2 SD and ranged from 28 to 74 years. Regarding performance status (PS) by SWOG classification 4 patients were classified as being PS 0, 49 patients were PS 1 and 4 patients were PS 2. Ten patients (17.5%) showed partial response (PR),24 patients (42.1%) showed stationary disease (SD), while 23 patients (40.4%) showed progressive disease (PD). The median progression free survival time was 8 months (95% CI 6.97-9.02months) and the median overall survival time was 16 months (95% CI 15.08-16.91 months). Regarding grade 3/4 treatment related toxicity during the entire study period (entire study period was defined as from study entry to 7 days after disease progression); there was no grade 3 or 4 hematological related toxicity. Grade 3/4 nausea and vomiting was observed in 5% (n = 3), fatigue in 10.5% (n = 6) and infection in 7% (n = 4) of study group CONCLUSION: Concurrent radiotherapy plus TMZ in the treatment of newly diagnosed GBM is effective and safe. Further larger prospective comparative studies are warranted to document this finding.

432P - Patterns and Efficacy of Bevacizumab Use Across Treatment Lines in Glioblastoma

ABSTRACT Aim: Use of bevacizumab in the management of glioblastoma multiforme (GMB) remains controversial. Currently in Canada, it is approved for recurrent GBM treatment. We describe the use of bevacizumab and analyses the efficacy across treatment lines in GBM. Methods: Patients (pts) diagnosed GBM (primary or secondary) from 2008-2014 and treated with bevacizumab were identified at McGill University Hospitals; demographics, diagnosis, and treatment pattern were collected via chart review. Primary endpoints were median progression-free survival (PFS) and overall survival (OS) estimated via Kaplan-Meier method. Secondary endpoint was toxicity. Grading of adverse events (AEs) were in accordance to CTCAE 4.0 criteria. Results: 64 pts were identified and their files were analyzed (40 males; median age at diagnosis 54 years, range 26-83). Majority had KPS score ≥70 (n = 56, 87.5%). 49 (76.6%) pts had primary and 15 (23.4%) had secondary GBM. Available MGMT testing was performed in 24 pts (methylated n = 10, 15.6%; unmethylated n = 14, 21.9%). 30 (46.9%) received bevacizumab in 1st line and 34 (53.1%) 2nd line and beyond (2L+). The median duration of bevacizumab in 1st line 36.6 weeks and 2L+ 14.21 weeks (overall 24.4 weeks; range Conclusions: Our results show bevacizumab treatment may be more efficient after a recurrence than when used in the beginning of treatment and are in line with reported registration trials data. Disclosure: All authors have declared no conflicts of interest.

P16.13 * UNCERTAINTY AND VARIABILITY IN SURVEILLANCE IMAGING AFTER COMPLETION OF PRIMARY TREATMENT IN GLIOBLASTOMA MULTIFORME

INTRODUCTION: Clear and evidence-based follow up imaging guideline after the completion of primary therapy in glioblastoma multiforme (GBM) is lacking. Here we provide the first report analysing international, national and local guidelines in GBM imaging surveillance. METHODS: First we performed a systematic review of GBM management guidelines indexed in PUBMED and EMBASE databases up until October 2013. We then searched for GBM guidelines on websites of the relevant international and national societies. Next, to ascertain local recommendations within the UK, we reviewed guideline documents produced by the local neuro-oncology multidisciplinary teams (MDTs; n = 28) in the UK accessed via the Care Quality Improvement Network (CQuIN) database. For all the relevant guidelines identified, we extracted imaging recommendations for the period following completion of primary therapy. RESULTS: Of identified guidelines produced by international and national societies, only 6 had follow up imaging guidelines with variability in imaging frequency ranging from 1-2 monthly (1 guideline), 2-4 monthly (1), 2-3 monthly (2), to 3-4 monthly (2). Twenty out of the 28 neuro-oncology MDTs had imaging guidelines. Of these, 18 had guidelines on imaging after completion of primary therapy, with also a wide variability in imaging frequency from 2 monthly (2 guidelines), 2-4 monthly (1), 3 monthly (6), 3-4 monthly (1), 3-6 monthly (2), 6 monthly (4), and yearly (2). Most guidelines did not include references to any evidence base to inform the recommendations. CONCLUSIONS: The guidelines and recommendations for follow up imaging after the completion of primary therapy in GBM are variable and uncertain. Future studies should assess effectiveness of these guidelines in detecting assymptomatic GBM recurrence.

Nanoparticles for hyperthermic therapy: synthesis strategies and applications in glioblastoma.

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Current GBM treatment includes surgery, radiation therapy, and chemotherapy, sometimes supplemented with novel therapies. Despite recent advances, survival of GBM patients remains poor. Major challenges in GBM treatment are drug delivery across the blood–brain barrier, restriction of damage to healthy brain tissues, and limitation of resistance to therapies. This article reviews recent advances in the application of magnetic nanoparticles (MNPs), gold nanorods (GNRs), and carbon nanotubes (CNTs) for hyperthermia ablation of GBM. First, the article introduces GBM, its current treatment, and hyperthermia as a potential modality for the management of GBM. Second, it introduces MNPs, GNRs, and CNTs as inorganic agents to induce hyperthermia in GBM. Third, it discusses different methodologies for synthesis of each inorganic agent. Finally, it reviews in vitro and in vivo studies in which MNPs, GNRs, and CNTs have been applied for hyperthermia ablation and drug delivery in GBM.

First combined intravenous and intracerebral application of an oncolytic virus, parvovirus h-1, in a phase I/IIa clinical trial in patients with recurrent glioblastoma multiforme (ParvOryx01).

TPS2111 Background: The management of glioblastoma multiforme (GBM) is an unsolved problem and medium survival has remained at dismal 15 months. Among alternative treatments is the use of oncolytic...

Activation of STAT5 contributes to proliferation in U87 human glioblastoma multiforme cells.

Rapid increases in the tyrosine phosphorylation of signal transducers and activators of transcription 5 (STAT5) proteins have been extensively documented in cells stimulated with cytokines and growth factors. However, the mechanisms by which STAT5 translocates to the nucleus and regulates proliferation in human glioblastoma multiforme cells have not been studied in detail. To the best of our knowledge, the present study demonstrated for first time that stimulation of a glioblastoma multiforme (GBM) cell line (U87-MG) with hepatocyte growth factor (HGF) resulted in the phosphorylation of STAT5 at Tyr-694/699 and nuclear translocation of STAT5. In addition, HGF promoted nuclear translocation of STAT5 in a time-dependent manner and increased the proliferation of U87-MG cells. In order to determine the role of STAT5 directly, RNA interference was used to knockdown STAT5 expression in the U87-MG cell line. It was illustrated that small interfering RNA (siRNA) against STAT5 successfully inhibited the protein expression of STAT5 in the U87-MG cell line, leading to a potent suppression of tumor cell proliferation with or without HGF treatment. In order to broaden the investigation and to determine the role of STAT5 invivo, immunohistochemistry (IHC) was applied to evaluate STAT5 expression in 100 newly diagnosed glioma and 10 non-neoplastic brain tissues. p-STAT5 expression increased according to the histopathological grade of the glioma. However, no p-STAT5 staining was observed in non-neoplastic brain tissues. These findings suggested that inhibition of the STAT5 pathway may be an effective therapeutic strategy for the clinical management of GBM.

Standards of care and novel approaches in the management of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?

Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (b-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.

Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?

Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (β-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.

NetGestalt: integrating multidimensional omics data over biological networks

NetGestalt: integrating multidimensional omics data over biological networks

The influence of regional health system characteristics on the surgical management and receipt of post operative radiation therapy for glioblastoma multiforme

Despite a known optimal treatment protocol for the management of glioblastoma multiforme (GBM), many patients fail to receive complete surgical resection or post-operative radiation therapy (PORT). The underlying reasons behind this disparity are unclear. Our study investigates the influence of regional health system resources on the surgical management and PORT receipt in patients with GBM. Surgical intervention, PORT receipt and patient data for patients diagnosed with GBM were obtained from the years 2004 to 2008 from the NCI Surveillance, Epidemiology, and End Results database and combined with the health system data from the Area Resource File. Four logistic models were constructed to test the effect of health system characteristics on surgical treatment choice and PORT receipt among health service areas (HSAs). We found that younger, married patients in HSAs with higher median incomes were significantly more likely to receive both gross total resection (p < 0.001, p < 0.001, p = 0.002) and PORT (p < 0.001, p < 0.001, p = 0.008). The density of radiation oncology equipped hospitals was also a significant predictor of PORT receipt (p = 0.002). Our findings suggest regional variations in of neuro-oncology services and income may have impact on GBM management. Policies aimed at narrowing disparities in treatment may need to focus on addressing regional variations in oncology resources.

Current Advances in Radiotherapy for Newly Diagnosed Glioblastoma Multiforme

Glioblastoma multiforme is the most common adult primary brain tumor that is associated with very poor survival. The current standard therapy for newly diagnosed glioblastoma multiforme includes surgical resection and a combination of radiotherapy and chemotherapy with temozolomide. This treatment strategy leads to better overall survival; however, majority of tumor recurrences occur within the irradiated field. To overcome this problem, dose intensification is being tested in the management of glioblastoma multiforme. In recent years, technological development of radiotherapies, such as intensity-modulated radiation therapy, stereotactic radio surgery, stereotactic radiation therapy, boron neutron capture therapy, and particle beam therapy, has improved dose distribution. Several prospective studies using these radiotherapies have shown that dose escalation is feasible and appears to be effective. Although the number of patients with glioblastoma multiforme in each study was not large, the survival times in these studies tended to be better than in those with standard dosing schedules. Dose escalation radiotherapy could be a hopeful strategy for patients with glioblastoma multiforme. In this review, we review advances in current radiotherapies for patients with newly diagnosed glioblastoma multiforme.

Long-Term Survival and Improved Quality of Life following Multiple Repeat Gamma Knife Radiosurgeries for Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

The management of glioblastoma multiforme (GBM) is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS) as a salvage treatment. In this clinical situation, three sequential GKRS treatments led to prolonged survival (beyond four years after diagnosis) and improved quality of life in a patient who was unable to receive further chemotherapy regimens and was unwilling to undergo further aggressive resection. To date, there have been few reports of three or more sequential GKRS treatment sessions utilized as salvage therapy for recurrent GBM in patients who can no longer tolerate chemotherapy. This report provides evidence that aggressive local treatment with GKRS at the time of recurrence may be appropriate, depending on a patient's individual clinical situation, and can lead to prolonged survival and improved quality of life.

Stereotactic Radiosurgery and Bevacizumab for Recurrent Glioblastoma Multiforme

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.

Abstract 1801: Lyn and Fyn inhibition as a potential novel treatment for glioblastoma multiforme

Abstract Background: Glioblastoma multiforme (GBM) is the most malignant and most aggressive of the adult brain tumors. The current therapies including surgical resection, radiation therapy and chemotherapy remain palliative with median survival of 14 months. Two of the Src family kinases, Lyn and Fyn, have been reported to be involved in the pathogenesis and aggressiveness of GBM in clinical and laboratory research studies. Specific Aims: We evaluated the effect of Lyn and Fyn kinase inhibition on GBM cell motility and survival by utilizing a clinically relevant Lyn and Fyn kinase inhibitor, bafetinib or formerly INNO-406 (CytRx Corporation, Los Angeles, CA). Bafetinib, a dual Bcr-Abl and Lyn tyrosine kinase inhibitor has been shown to inhibit 4 of the 79 tyrosine kinases, namely Abl, Abl-related gene (Arg), and two of the Src family kinases Lyn and Fyn but not Src. Methodology: We used Lyn- expressing T98G and Fyn-expressing U87MG human GBM cell lines. The effect of bafetinib on the motile activity was evaluated by the wound healing, single cell trajectory, and the trans-well assays. The cell survival and mitochondrial membrane potential were evaluated by Guava Easycyte *HT flowcytometer (Millipore) in cells treated with bafetinib for 24 h. Further, we examined the effect of bafetinib on cell survival in combination with temozolomide (TMZ), a widely used chemotherapy agent for the management of GBM, in U87MG cells using microplate MTT assay. Results: At 16 h post-wounding, bafetinib at 5 µM concentration inhibited the motility of T98G and U87MG cells by 33% (P &amp;lt; 0.01) and 24% (P &amp;lt; 0.01), respectively. This significant inhibition in the wound healing was accompanied by the inhibition of total length of cell trajectory, total length of the final cell displacement and average speed of cell locomotion. Bafetinib induced 62% mitochondrial membrane depolarization in U87MG cells and 20% depolarization in T98G cells. Higher depolarization levels in U87MG cells correlated with higher apoptosis (49.4%). Treatment of U87MG cells for 4 days with a combination of bafetinib and TMZ reduced the IC50 values as much as 60% and 80%, respectively, compared to the values obtained with each of the drugs, suggesting that bafetinib has the potential to improve the therapeutic effect of TMZ in GBM cells. Conclusion: Our preliminary findings suggest that targeting Lyn and Fyn kinase pathways with bafetinib may have a therapeutic potential for GBM. Our in vivo studies in mouse models with bafetinib will further establish the feasibility of targeting Lyn and Fyn kinases as possible therapeutic targets in GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1801. doi:1538-7445.AM2012-1801

Use of a Deformable Atlas to Identify Cryptic Critical Structures in the Treatment of Glioblastoma Multiforme

Dose constraints for traditional neural critical structures (e.g. optic chiasm, brain stem) are a standard component of planning radiation therapy to the central nervous system. Increasingly, investigators are becoming interested in accounting for the dose delivered to other non-target neural structures (e.g. hippocampi), which are not easily identified on axial imaging. In this pilot study, a commercially available digital atlas was used to identify cryptic neural structures (hippocampus, optic radiations, and visual cortices) in 6 patients who received intensity modulated radiation therapy (IMRT) as part of multimodal management of glioblastoma multiforme (GBM). The patient's original IMRT plans were re-optimized, with avoidance parameters for the newly identified critical structures. Re-optimization was able to reduce both mean and maximum dose to the volumes of interest, with a more pronounced effect for contralateral structures. Mean dose was reduced by 11% and 3% to contralateral and ipsilateral structures, respectively, with comparable reduction in maximum dose of 10% and 2%, respectively. Importantly, target coverage was not compromised, with an average change in coverage of 0.2%. Overall, our results demonstrate the feasibility of incorporating tools for cryptic critical structure identification into the treatment planning process for GBM.

Glioblastoma multiforme: Molecular characterization and current treatment strategy (Review)

Glioblastoma multiforme (GBM) is the most common and lethal malignant primary brain tumor. It is classified by the World Health Organization (WHO) in the group of diffusely infiltrating astrocytomas, representing up to 50% of all primary brain gliomas, and carries the poorest prognosis. Aberrant genetic events and signaling pathways have clearly demonstrated that GBM is highly anaplastic and a morphologically highly heterogeneous tumor. Understanding the genetic alterations, specific molecular biomarkers and proliferative pathways may promote therapeutic development for the management of GBM. Age, Karnofsky performance score, histology, position and the extent of tumor resection have been identified as potential prognostic factors for patients with GBM. In this study, we review the molecular characterization of tumor cells, the current standard of care for patients diagnosed with GBM, including gross or near-total resection of the tumor, followed by radiotherapy, stereotactic brachytherapy, chemotherapy and new targeted therapies. Thus, we conclude that multimodal approaches for the treatment of patients with GBM may significantly improve their prognoses.

The challenges of managing glioblastoma multiforme in developing countries: a trade-off between cost and quality of care

The management of glioblastoma multiforme (GBM) in developing countries is hindered by the paucity of clear protocols due in part to growing economic constraints and the lack of availability of expensive chemotherapeutic agents. We evaluated the deliverable treatment protocols and achievable outcomes for patients with GBM in a low-income country prior and subsequent to the worldwide adoption of temozolomide. Retrospective case series. Charts of consecutive patients with a pathologic diagnosis of high-grade glioma diagnosed between January 2003 and December 2008 were retrospectively reviewed. We identified 146 adult patients, including 105 males and 41 females between 19 and 81 years of age (median age, 51 years), with histologically confirmed high-grade glioma. All patients underwent craniotomy. Eighty-two patients were treated with radiotherapy and temozolomide, of whom 42 patients received temozolomide concurrent with radiation followed by adjuvant temozolomide; 40 patients received irradiation followed sequentially by 6 cycles of temozolomide. In 40 patients irradiation was utilized as a single modality treatment adjuvant to surgery. The follow-up ranged from 1 to 56 months (median, 9.4 months). The median survival for the whole cohort was 10.2 months. The median survival for the radiotherapy-alone group was 5.3 months and for combined radiotherapy/temozolomide was 14.8 months. Survival was similar in both concurrent and sequential groups. Temozolomide conferred a statistically significant survival benefit of 9 months compared with standard therapeutic modalities. The results compare favorably to those reported in developed nations. Current management of GBM in developing countries should include maximal surgical resection followed by radiotherapy/temozolomide whenever medically and/or financially feasible. Outcomes comparable to those obtained within the context of randomized trials can be expected in low-income settings if healthcare delivery is carefully planned. Our results indicate that concurrent and sequential regimens are equally effective in these patients.

Epidermal Growth Factor Receptor Expression Modulates Antitumor Efficacy of Vandetanib or Cediranib Combined With Radiotherapy in Human Glioblastoma Xenografts

The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression. Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers. In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib. EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a "personalized" approach to GBM management.