0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Recent Advances in Therapy for Glioblastoma FREE

Jennifer Clarke, MD, MPH; Nicholas Butowski, MD; Susan Chang, MD
[+] Author Affiliations

Section Editor: David E. Pleasure, MD
Author Affiliations:Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco.

More Author Information
Arch Neurol. 2010;67(3):279-283. doi:10.1001/archneurol.2010.5.
Text Size: A A A
Published online

Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. Despite that, recurrence is quite common, and so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review recent advances in therapy for glioblastoma, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of glioblastoma is discussed in a separate article in this issue of the Archives.

Figures in this Article

Approximately 51 000 primary brain tumors are diagnosed in the United States each year, 36% of which are gliomas.1Of these, half are glioblastoma (GBM), or World Health Organization grade IV astrocytoma. Glioblastoma is the most aggressive form of glioma and, despite recent advances, continues to have a grim prognosis. The current standard of care for GBM begins with maximal safe surgical resection. After surgery, the combination of radiotherapy (RT) with temozolomide followed by adjuvant temozolomide therapy was shown to be significantly, although modestly, better than RT alone in a phase 3 clinical trial coordinated by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada.2Median overall survival in the chemoradiotherapy arm was 14.6 months compared with 12 months in the RT arm. Perhaps more importantly, however, the percentage of patients alive at 2 years increased from approximately 10% to approximately 26%.

A post hoc analysis of tumor tissue in a subset of patients in the phase 3 trial demonstrated that patients whose tumors have methylation of the promoter region of the methylguanine methyltransferase (MGMT) gene (GenBank 4255) survived longer than those whose tumors were not methylated and on average derived greater benefit from the addition of temozolomide to RT.3However, temozolomide provided modest benefit in the nonmethylated group, with borderline statistical significance. There is currently no proven alternative treatment for patients with nonmethylated tumors, so the combination of RT and temozolomide remains the treatment of choice for all patients with GBM at this time.

However, the median progression-free survival after RT with temozolomide and adjuvant temozolomide therapy is only 7 months, and a subset of patients' tumors show inexorable growth despite combined chemoradiotherapy. Therefore, we continue to search for more effective treatments to treat this difficult disease. This article will review recent advances in the treatment of GBM.

Prospective surgical trials are very difficult to design and implement and, as such, few have been attempted. One recent multicenter phase 3 study from Germany evaluated the utility of 5-aminolevulinic acid (a fluorescent label) to assist surgeons in achieving a radiographic gross total resection of the contrast-enhancing portion of GBM.4Only patients with ring-enhancing tumors that were believed to be potentially fully resectable were eligible to participate. All patients underwent maximal resection of tumor; they were randomized to the use of standard white light or fluorescence for intraoperative guidance. Use of 5-aminolevulinic acid allowed for a significantly higher rate of complete resection of enhancing disease on postoperative magnetic resonance imaging performed within 72 hours of surgery; gross total resection was achieved in 65% of patients in the treatment arm compared with 35% in the conventional surgery arm.

Further analysis of the data from this trial has demonstrated that patients who underwent gross total resection, regardless of the treatment arm, had superior survival to those who received subtotal resection.5Although prospective data specifically addressing the issue of surgical extent of resection have never been collected, it is fairly well accepted at this point that cytoreduction via maximal safe resection improves survival. It also appears that use of 5-aminolevulinic acid intraoperatively may help to maximize resection.

The standard of care for RT for GBM is focal, fractionated external beam RT (EBRT), but new techniques and technologies continue to be evaluated. Although no prospective, randomized studies have compared the 2 techniques, intensity-modulated RT (IMRT) is becoming widely used and appears to be fairly comparable to more traditional 3-dimensional EBRT.6A number of dose-intensification techniques, such as brachytherapy, hyperfractionation, and the combination of EBRT with stereotactic radiation “boosts,” have been investigated, but none has been clearly shown to be superior to standard EBRT.

Treatment of GBM can be divided into 2 major situations: initial treatment and treatment at disease recurrence. New agents or treatment delivery techniques are typically tested first in the recurrent disease setting, where there are few approved treatment alternatives. Promising agents may then be combined with EBRT and temozolomide in the initial treatment setting because this is the established standard of care.

Alkylating Agents

Many GBMs have or develop resistance to alkylating chemotherapeutic agents such as temozolomide. One common mechanism of resistance is mediated by the enzyme encoded by the MGMTgene, O6-alkylguanine-DNA alkyltransferase. Methylation of the promoter region of the gene silences it, leading to greater sensitivity to temozolomide. One promising strategy for overcoming resistance is simply administering more frequent temozolomide doses in what are referred to as dose-dense or dose-intense schedules.7The Radiation Therapy Oncology Group has recently completed a phase 3 study randomizing patients between the standard 5-day regimen of temozolomide and a dose-intense 21-day monthly regimen of temozolomide after chemoradiotherapy; results are pending. Another strategy is direct enzyme inhibition using O6-benzylguanine, which has been studied in combination with temozolomide.8A second mechanism of resistance is mediated by the poly(adenosine diphosphate–ribose) polymerase (PARP) system; a number of PARP inhibitors have been developed and are being tested in early-phase clinical trials in combination with RT and temozolomide therapy.

Molecularly Targeted Agents

As we learn more about the biology of GBM and its aberrant signaling pathways, the neuro-oncology community has begun to investigate the role of molecularly targeted agents inhibiting these pathways (Figure). Most of the targeted agents are small-molecule tyrosine kinase inhibitors9or monoclonal antibodies. The signaling pathways targeted include tumor growth factor pathways, angiogenesis pathways, and the intracellular signaling pathways that lie downstream of both. The angiogenesis pathways and their associated antiangiogenic agents are covered separately in this issue of the Archives.10

Place holder to copy figure label and caption
Figure.

Selected growth factor pathways demonstrating targets for new molecular agents, with examples of agents currently under study. EGFR indicates epidermal growth factor receptor; GDP, guanosine diphosphate; Grb2, growth factor receptor-bound 2; GTP, guanosine triphosphate; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; mTOR, mammalian target of rapamycin; P, phosphate group; PDGFR, platelet-derived growth factor receptor; PDK, phosphatidylinositol-dependent kinase; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol 4,5-bisphosphate, PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphate and tensin homologue; and TSC, tuberous sclerosis complex.

Graphic Jump Location

A wide variety of targeted agents are being studied in the preclinical setting and in clinical trials. The overall experience at this point has been that monotherapy at recurrence with highly targeted tyrosine kinase inhibitors of all types has shown limited efficacy. It remains an open question for many of these agents whether molecular selection of tumors with particular mutations in the pertinent pathway may optimize efficacy; results of this type of strategy thus far have been mixed. Overall survival in multiple recent single-arm studies combining targeted agents with EBRT and temozolomide for first-line treatment has been modestly superior relative to historical controls. Because results with highly targeted agents have been somewhat disappointing, there has been a move toward combined inhibition of multiple targets, shutting down proximal and distal targets within the same pathway or shutting down targets in separate, parallel pathways. This can be accomplished via a combination of multiple agents or via single agents that inhibit multiple kinases. The potential for greater efficacy by inhibiting multiple pathways is counterbalanced by the corresponding increase in the risk of toxic effects from systemic inhibition of these same pathways.

Epidermal Growth Factor.Epidermal growth factor (EGF) and its receptor, EGFR, have been implicated in the growth of a number of tumors, including GBM. Binding of the EGF ligand to the extracellular portion of the EGFR activates the intracellular tyrosine kinase domain, triggering a variety of signaling cascades. Abnormally increased EGFR signaling activity is frequent in GBMs; it can be the result of overexpression due to polysomy or amplification or the result of mutation (eg, the EGFRvIII mutant, seen in roughly 40% of GBMs, has a constitutively active tyrosine kinase domain owing to a deletion in the extracellular binding domain). Antibodies to EGFR such as cetuximab are currently under evaluation in early-phase clinical trials. The small-molecule EGFR inhibitor erlotinib hydrochloride has been more extensively evaluated as a single agent in recurrent disease and in combination with RT and temozolomide for initial treatment. Results have been disappointing in recurrent disease11and mixed in initial treatment, with one study suggesting mildly improved survival12but a second study failing to show improvement.13

Additional studies to evaluate EGFR inhibitors in combination with other agents are ongoing, as are prospective studies to evaluate subpopulations that may be more likely to derive benefit from this class of agents. Two retrospective studies have found a correlation between activity of the protein kinase B/AKT pathway and erlotinib response in tumors with overexpression of EGFR, although this has not been confirmed prospectively.14,15

Platelet-Derived Growth Factor.Platelet-derived growth factor (PDGF) and its receptor (PDGFR) are also commonly overactive in GBM, and, like activation of EGFR, activation of PDGFR triggers multiple intracellular signaling cascades. Imatinib mesylate is the best-known PDGFR inhibitor, although it also inhibits BCR-ABL and c-KIT. Phase 2 studies have evaluated imatinib in recurrent GBM as a single agent16and in combination with hydroxyurea,17but again, as with EGFR inhibitors, the results have been disappointing overall.

Hepatocyte Growth Factor/Scatter Factor.Hepatocyte growth factor (also known as scatter factor) binds to the c-MET receptor, activating intracellular signaling cascades similar to those triggered by EGFR and PDGFR; c-MET signaling is thought to be associated with invasion. In addition to stimulating c-MET, hepatocyte growth factor activates the EGF and vascular endothelial growth factor pathways. Multiple c-MET inhibitors are currently under evaluation; one, AMG102, is a human monoclonal antibody against hepatocyte growth factor that is currently in phase 2 study. Several small-molecule inhibitors are also currently under investigation.

Phosphoinositide-3 Kinase/AKT/Mammalian Target of Rapamycin Pathway.One of the intracellular second-messenger systems activated by EGFR, PDGFR, and the c-MET receptor is the phosphoinositide-3 kinase pathway, which leads to activation of AKT, also called protein kinase B, and then several targets further downstream, including the mammalian target of rapamycin. The major negative regulator of this pathway is the phosphate and tensin homologue (PTEN); there is frequently mutation of the PTENgene (GenBank 5728) or loss of heterozygosity of the chromosome on which the PTENgene resides in GBM, likely contributing to the overactivity of this pathway. Temsirolimus and everolimus are both inhibitors of the mammalian target of rapamycin, the best-studied of the targets in the phosphoinositide-3 kinase pathway. Temsirolimus as monotherapy was well tolerated but showed little efficacy in recurrent GBM18; combination studies with multiple other agents are ongoing. Perifosine is a direct AKT inhibitor and is also under evaluation in recurrent malignant glioma.

RAS/RAF/Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase Pathway.Another second-messenger system activated by EGFR and PDGFR begins with the RAS protein, which initiates a number of signaling cascades, including that of mitogen-activated protein kinase, which has been implicated in cell proliferation. Farnesyl transferase inhibitors inhibit the enzyme that activates RAS; the most extensively studied in GBM is tipifarnib (R115777), which was well tolerated with modest activity as a single agent19and is currently being studied in combination with several other agents.

Epigenetic Alterations.The importance of epigenetic alterations in tumors is being increasingly appreciated. For example, histone deacetylases, enzymes that play a role in the chromatin structure that organizes DNA and regulates gene transcription, are known to have a role in multiple cancers, including GBM. Vorinostat, a histone deacetylase inhibitor, has shown modest benefit as a single agent in GBM20and is currently being tested in combination regimens.

Methods for Local Drug Delivery

One of the major challenges of chemotherapy for GBM is the achievement of adequate drug concentration within the tumor itself. The blood-brain barrier, although often impaired in areas of bulky tumor, still acts as a barrier against many drugs, particularly in the periphery of the tumor, which is often highly infiltrative. Therefore, a variety of alternative delivery methods have been evaluated. One such method is the placement of drug-containing wafers. Carmustine (bischloroethylnitrosourea) is a nitrosourea compound, and carmustine-impregnated wafers (Gliadel wafers; MGI Pharma, Bloomington, Minnesota) have been placed into the surgical cavity after tumor resection, with modest efficacy.21The combination of carmustine-impregnated wafer placement with EBRT and temozolomide has not been formally studied, although it appears well tolerated.22

Convection-enhanced delivery is another strategy for local drug delivery. The technique involves the placement of several catheters into a surgical cavity immediately after resection; antineoplastic agents are then delivered through the catheters using convection, which improves distribution within the surrounding tissue where residual tumor cells persist. Early-phase studies using convection-enhanced delivery to deliver cintredekin besudotox (a recombinant protein combining portions of the interleukin 13 and Pseudomonasexotoxin proteins) in patients with recurrent malignant gliomas have been promising,23although neither it nor any other agent administered via this technique has received approval yet.

Immunotherapeutic treatment for glioma includes active and passive strategies. Active immunotherapy upregulates an immune response to tumor and can confer long-term immunity that potentially continues to provide protection against future tumor recurrence. Passive immunotherapy involves the transfer of immune effectors to achieve an immediate effect but does not generate long-term immunity.

Active Immunotherapy

A variety of strategies are being pursued to induce cytokine secretion directly within tumors because systemic exposure leads to excessive toxic effects. Techniques using direct cell transplants or genetically engineered viral vectors to induce cytokine production within GBM are currently undergoing preclinical evaluation.24Another area of active research is that of pattern recognition receptors and their agonists.25Double-stranded RNA (dsRNA), a nucleic acid variant normally associated with viruses, is one such agonist. A few clinical trials using poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose), a dsRNA moiety, have included patients with GBM and have been published, with mixed results.26,27

Tumor vaccines attempt to induce the immune system to generate a response against the tumor. One of the few known truly tumor-specific antigens is EGFRvIII. A peptide vaccine in which the sequence encompasses the mutated segment of EGFRvIII has demonstrated a cytotoxic response against gliomas in preclinical studies.28This vaccine, in combination with RT and temozolomide, is being studied in a phase 2/3 trial for patients with newly diagnosed tumors that contain the mutation in question. Several other promising tumor vaccine strategies are also being used in clinical trials.29

Dendritic cells are professional antigen-presenting cells that can be primed with tumor antigen ex vivo30and then readministered to the patient, where they mediate T-cell activation. Numerous preclinical studies demonstrate that dendritic cells pulsed with glioma antigens can prime a cytotoxic lymphocyte response that is tumor specific; phase 1 and 2 clinical trials have been completed using dendritic cell strategies, with encouraging results.31

Passive Immunotherapy

Antibody-mediated drug delivery is a strategy designed with the dual purpose of increasing the local drug concentration while minimizing nonspecific systemic exposure. Monoclonal antibodies targeting glioma-specific structures have been coupled to radionuclides (radioimmunoconjugates), exotoxins (immunotoxins), or chemotherapeutic agents and are administrated locally. Antigens that are overexpressed in tumors relative to normal tissue are typically used, such as mutant EGFR, tenascin, and interleukin 4 or interleukin 13 receptors.32

Gene therapy is based on the insertion or modification of genes into a cell to treat a disease. Gene delivery can be accomplished using a variety of vectors, from viruses to cell-based systems to synthetic vectors. In gliomas, viral vectors have been used to deliver suicide genes, proapoptotic genes, p53, cytokines, and caspases.33Such studies have shown promising preclinical results, but clinical trials have been limited by the fact that transduced cells were found only within a very short distance of the delivery site. Synthetic vector research has focused on the use of nanoparticles. Liposomal vectors, for example, have been used to deliver therapeutic genes in the preclinical setting.

A variety of other novel therapeutic approaches are also currently being researched, including the use of alternating electrical fields to disrupt cell division via a device called NovoTTF-100A (NovoCure Ltd, Haifa, Israel),34currently in phase 3 trials, and the use of thermal lasers to denature tumor tissue.

In conclusion, the survival of patients with GBM continues to improve, albeit more slowly than we would like. A wide variety of new techniques and agents are currently under study, alone and in combination. Increased collective experience in their use and improved understanding of the complex biology of GBM may allow for more rational and effective therapy selection for patients, further extending survival in the years to come.

Correspondence:Jennifer Clarke, MD, MPH, Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, 400 Parnassus Ave, Room A-808, Box 0372, San Francisco, CA 94143-0372 (clarkej@neurosurg.ucsf.edu).

Accepted for Publication:October 15, 2009.

Author Contributions:Study concept and design: Clarke, Butowski, and Chang. Drafting of the manuscript: Clarke and Butowski. Critical revision of the manuscript for important intellectual content: Clarke, Butowski, and Chang. Administrative, technical, and material support: Clarke and Butowski. Study supervision: Butowski and Chang.

Financial Disclosures:Dr Clarke has been a consultant for Schering-Plough. Dr Chang has received research funding from Genentech, Novartis, and Schering-Plough.

Additional Contributions:Ilona Garner, BS, provided editorial assistance in the preparation of this manuscript.

Central Brain Tumor Registry of the United States, 2007-2008 Statistical report: primary brain tumors in the United States, 2000-2004. http://www.cbtrus.org/reports/reports.html. Accessed October 1, 2009
Stupp  RMason  WPvan den Bent  MJ  et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352 (10) 987- 996
PubMed Link to Article
Hegi  MEDiserens  ACGorlia  T  et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352 (10) 997- 1003
PubMed Link to Article
Stummer  WPichlmeier  UMeinel  TWiestler  ODZanella  FReulen  HJALA-Glioma Study Group, Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7 (5) 392- 401
PubMed Link to Article
Pichlmeier  UBink  ASchackert  GStummer  WALA Glioma Study Group, Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 2008;10 (6) 1025- 1034
PubMed Link to Article
Narayana  AYamada  JBerry  S  et al.  Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results. Int J Radiat Oncol Biol Phys 2006;64 (3) 892- 897
PubMed Link to Article
Clarke  JLIwamoto  FMSul  J  et al.  Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 2009;27 (23) 3861- 3867
PubMed Link to Article
Quinn  JAJiang  SXReardon  DA  et al.  Phase II trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 2009;27 (8) 1262- 1267
PubMed Link to Article
Chi  ASWen  PY Inhibiting kinases in malignant gliomas. Expert Opin Ther Targets 2007;11 (4) 473- 496
PubMed Link to Article
Iwamoto  FMFine  HA Bevacizumab for malignant gliomas. Arch Neurol 2010;67 (3) 285- 288
Link to Article
van den Bent  MJBrandes  AARampling  R  et al.  Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC Brain Tumor Group Study 26034. J Clin Oncol 2009;27 (8) 1268- 1274
PubMed Link to Article
Prados  MDChang  SMButowski  N  et al.  Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 2009;27 (4) 579- 584
PubMed Link to Article
Brown  PDKrishnan  SSarkaria  JN  et al. North Central Cancer Treatment Group Study N0177, Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008;26 (34) 5603- 5609
PubMed Link to Article
Haas-Kogan  DAPrados  MDTihan  T  et al.  Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97 (12) 880- 887
PubMed Link to Article
Mellinghoff  IKWang  MYVivanco  I  et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353 (19) 2012- 2024
PubMed Link to Article
Wen  PYYung  WKLamborn  KR  et al.  Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006;12 (16) 4899- 4907
PubMed Link to Article
Reardon  DAEgorin  MJQuinn  JA  et al.  Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme [published correction appears in J Clin Oncol. 2006;24(7):1224]. J Clin Oncol 2005;23 (36) 9359- 9368
PubMed Link to Article
Galanis  EBuckner  JCMaurer  MJ  et al. North Central Cancer Treatment Group, Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005;23 (23) 5294- 5304
PubMed Link to Article
Cloughesy  TFWen  PYRobins  HI  et al.  Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 2006;24 (22) 3651- 3656
PubMed Link to Article
Galanis  EJaeckle  KAMaurer  MJ  et al.  Phase II trial of vorinostat in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2009;27 (12) 2052- 2058
PubMed Link to Article
Hart  MGGrant  RGarside  RRogers  GSomerville  MStein  K Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev 2008; (3) CD007294
PubMed
McGirt  MJThan  KDWeingart  JD  et al.  Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 2009;110 (3) 583- 588
PubMed Link to Article
Kunwar  SPrados  MDChang  SM  et al. Cintredekin Besudotox Intraparenchymal Study Group, Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 2007;25 (7) 837- 844
PubMed Link to Article
Mitchell  DAFecci  PESampson  JH Immunotherapy of malignant brain tumors. Immunol Rev 2008;22270- 100
PubMed Link to Article
Lotfi  RSchrezenmeier  HLotze  MT Immunotherapy for cancer: promoting innate immunity. Front Biosci 2009;14818- 832
PubMed Link to Article
Butowski  NChang  SMJunck  L  et al.  A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05). J Neurooncol 2009;91 (2) 175- 182
PubMed Link to Article
Salazar  AMLevy  HBOndra  S  et al.  Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study. Neurosurgery 1996;38 (6) 1096- 1104
PubMed
Choi  BDArcher  GEMitchell  DA  et al.  EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol 2009;19 (4) 713- 723
PubMed Link to Article
Yamanaka  R Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol Med 2008;14 (5) 228- 235
PubMed Link to Article
Luptrawan  ALiu  GYu  JS Dendritic cell immunotherapy for malignant gliomas. Rev Recent Clin Trials 2008;3 (1) 10- 21
PubMed Link to Article
Selznick  LAShamji  MFFecci  PGromeier  MFriedman  AHSampson  J Molecular strategies for the treatment of malignant glioma: genes, viruses, and vaccines. Neurosurg Rev 2008;31 (2) 141- 155
PubMed Link to Article
Mitchell  DASampson  JH Toward effective immunotherapy for the treatment of malignant brain tumors. Neurotherapeutics 2009;6 (3) 527- 538
PubMed Link to Article
Germano  IMBinello  E Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J Neurooncol 2009;93 (1) 79- 87
PubMed Link to Article
Kirson  EDDbaly  VTovarys  F  et al.  Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A 2007;104 (24) 10152- 10157
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Selected growth factor pathways demonstrating targets for new molecular agents, with examples of agents currently under study. EGFR indicates epidermal growth factor receptor; GDP, guanosine diphosphate; Grb2, growth factor receptor-bound 2; GTP, guanosine triphosphate; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; mTOR, mammalian target of rapamycin; P, phosphate group; PDGFR, platelet-derived growth factor receptor; PDK, phosphatidylinositol-dependent kinase; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol 4,5-bisphosphate, PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphate and tensin homologue; and TSC, tuberous sclerosis complex.

Graphic Jump Location

Tables

References

Central Brain Tumor Registry of the United States, 2007-2008 Statistical report: primary brain tumors in the United States, 2000-2004. http://www.cbtrus.org/reports/reports.html. Accessed October 1, 2009
Stupp  RMason  WPvan den Bent  MJ  et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352 (10) 987- 996
PubMed Link to Article
Hegi  MEDiserens  ACGorlia  T  et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352 (10) 997- 1003
PubMed Link to Article
Stummer  WPichlmeier  UMeinel  TWiestler  ODZanella  FReulen  HJALA-Glioma Study Group, Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7 (5) 392- 401
PubMed Link to Article
Pichlmeier  UBink  ASchackert  GStummer  WALA Glioma Study Group, Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 2008;10 (6) 1025- 1034
PubMed Link to Article
Narayana  AYamada  JBerry  S  et al.  Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results. Int J Radiat Oncol Biol Phys 2006;64 (3) 892- 897
PubMed Link to Article
Clarke  JLIwamoto  FMSul  J  et al.  Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 2009;27 (23) 3861- 3867
PubMed Link to Article
Quinn  JAJiang  SXReardon  DA  et al.  Phase II trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 2009;27 (8) 1262- 1267
PubMed Link to Article
Chi  ASWen  PY Inhibiting kinases in malignant gliomas. Expert Opin Ther Targets 2007;11 (4) 473- 496
PubMed Link to Article
Iwamoto  FMFine  HA Bevacizumab for malignant gliomas. Arch Neurol 2010;67 (3) 285- 288
Link to Article
van den Bent  MJBrandes  AARampling  R  et al.  Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC Brain Tumor Group Study 26034. J Clin Oncol 2009;27 (8) 1268- 1274
PubMed Link to Article
Prados  MDChang  SMButowski  N  et al.  Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 2009;27 (4) 579- 584
PubMed Link to Article
Brown  PDKrishnan  SSarkaria  JN  et al. North Central Cancer Treatment Group Study N0177, Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008;26 (34) 5603- 5609
PubMed Link to Article
Haas-Kogan  DAPrados  MDTihan  T  et al.  Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97 (12) 880- 887
PubMed Link to Article
Mellinghoff  IKWang  MYVivanco  I  et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353 (19) 2012- 2024
PubMed Link to Article
Wen  PYYung  WKLamborn  KR  et al.  Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006;12 (16) 4899- 4907
PubMed Link to Article
Reardon  DAEgorin  MJQuinn  JA  et al.  Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme [published correction appears in J Clin Oncol. 2006;24(7):1224]. J Clin Oncol 2005;23 (36) 9359- 9368
PubMed Link to Article
Galanis  EBuckner  JCMaurer  MJ  et al. North Central Cancer Treatment Group, Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005;23 (23) 5294- 5304
PubMed Link to Article
Cloughesy  TFWen  PYRobins  HI  et al.  Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 2006;24 (22) 3651- 3656
PubMed Link to Article
Galanis  EJaeckle  KAMaurer  MJ  et al.  Phase II trial of vorinostat in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2009;27 (12) 2052- 2058
PubMed Link to Article
Hart  MGGrant  RGarside  RRogers  GSomerville  MStein  K Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev 2008; (3) CD007294
PubMed
McGirt  MJThan  KDWeingart  JD  et al.  Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg 2009;110 (3) 583- 588
PubMed Link to Article
Kunwar  SPrados  MDChang  SM  et al. Cintredekin Besudotox Intraparenchymal Study Group, Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 2007;25 (7) 837- 844
PubMed Link to Article
Mitchell  DAFecci  PESampson  JH Immunotherapy of malignant brain tumors. Immunol Rev 2008;22270- 100
PubMed Link to Article
Lotfi  RSchrezenmeier  HLotze  MT Immunotherapy for cancer: promoting innate immunity. Front Biosci 2009;14818- 832
PubMed Link to Article
Butowski  NChang  SMJunck  L  et al.  A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05). J Neurooncol 2009;91 (2) 175- 182
PubMed Link to Article
Salazar  AMLevy  HBOndra  S  et al.  Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study. Neurosurgery 1996;38 (6) 1096- 1104
PubMed
Choi  BDArcher  GEMitchell  DA  et al.  EGFRvIII-targeted vaccination therapy of malignant glioma. Brain Pathol 2009;19 (4) 713- 723
PubMed Link to Article
Yamanaka  R Cell- and peptide-based immunotherapeutic approaches for glioma. Trends Mol Med 2008;14 (5) 228- 235
PubMed Link to Article
Luptrawan  ALiu  GYu  JS Dendritic cell immunotherapy for malignant gliomas. Rev Recent Clin Trials 2008;3 (1) 10- 21
PubMed Link to Article
Selznick  LAShamji  MFFecci  PGromeier  MFriedman  AHSampson  J Molecular strategies for the treatment of malignant glioma: genes, viruses, and vaccines. Neurosurg Rev 2008;31 (2) 141- 155
PubMed Link to Article
Mitchell  DASampson  JH Toward effective immunotherapy for the treatment of malignant brain tumors. Neurotherapeutics 2009;6 (3) 527- 538
PubMed Link to Article
Germano  IMBinello  E Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J Neurooncol 2009;93 (1) 79- 87
PubMed Link to Article
Kirson  EDDbaly  VTovarys  F  et al.  Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A 2007;104 (24) 10152- 10157
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 86

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles