Neurological Oncology
Read Time: 3 mins

Advances in Treatment Options for High-grade Glioma—Current Status and Future Perspectives

Copy Link
Published Online: Jun 4th 2011 US Neurology, 2010;6(1):55-63 DOI:
Authors: Ryan T Merrell, Eudocia C Quant, Patrick Y Wen
Quick Links:
Article Information

High-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplatic oligodendroglioma and anaplastic oligoastrocytoma, account for the majority of malignant primary brain tumours diagnosed in adults. The prognosis for these tumours is poor despite multimodality therapy with surgery, radiation and/or chemotherapy. This review summarises treatment options for high-grade glioma, including standard regimens, targeted agents and novel therapies.
Acknowledgement: The authors gratefully acknowledge the support of the Jim Kenary Brain Tumor Research Fund.


High-grade glioma, radiation therapy, chemotherapy, targeted molecular therapies


High-grade glioma (HGG) is the most common type of primary brain tumour in adults and accounts for >75% of the estimated 22,070 newly diagnosed malignant primary brain tumours in the US each year.1 More than half of HGGs are glioblastoma (GBM), the most aggressive subtype. The remainder include anaplastic gliomas (AGs),1,2 such as anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), and rarer subtypes. HGG is incurable and is responsible for a disproportionate share of cancer-related morbidity and mortality.3 With optimal treatment, median survival is only 12–18 months for GBM and two to five years for AG. There have been recent advances in elucidating the molecular pathogenesis of HGG, which may provide additional prognostic information and lead to more effective treatments.4–10 This article summarises the standard treatment of adult HGG with a particular focus on recent therapeutic advances.

Standard Treatment Options for High-grade Glioma
Surgery for High-grade Glioma

Maximal surgical resection is recommended in all newly diagnosed HGG patients. Although a surgical cure is impossible, benefits of resection include improvement of symptoms related to mass effect, reduction of tumour volume11 and removal of the necrotic tumour core, which may be resistant to radiation therapy and poorly accessible to circulating chemotherapy. Mounting evidence suggests that a near gross total resection confers a modest survival benefit compared with biopsy or subtotal resection.12–14
Surgery may be considered in recurrent HGG patients with good performance status when the tumour is accessible, symptomatic and distant from eloquent areas. Surgical resection in the recurrent setting may improve quality of life and allow time for additional therapy, but the impact on overall survival is negligible.

Radiation Therapy for High-grade Glioma

Radiation therapy (RT) has the biggest impact on overall survival for HGG of all standard treatment modalities. The addition of RT to surgery for glioblastoma (GBM) increases median survival from three to four months to approximately 12 months.15,16
Many variations of standard RT have been investigated in an attempt to increase efficacy, including using doses >60Gy, altered fractionation schemes, brachytherapy, stereotactic radiosurgery (SRS) and the use of radiosensitising agents. None of these has demonstrated additional benefit over standard fractionated RT.17,18 Newer approaches including chemotherapy,19 targeted molecular agents20 and anti-angiogenic agents21 may potentially work synergistically with RT and improve outcomes.
Additional involved-field RT is rarely offered to patients with recurrent HGG, as doses >60Gy offer marginal benefit and an increased risk of radiation necrosis.22 Small non-randomised studies have demonstrated a survival benefit for HGG patients treated with SRS at recurrence.23 However, many of the data are subject to selection bias, and this approach is not routinely utilised. Fractionated stereotactic RT has also been evaluated for treatment of recurrent HGG, but its efficacy is also unproven.24

Chemotherapy for Glioblastoma

Temozolomide has replaced nitrosureas as the standard of care for treatment of newly diagnosed GBM, based on the results of a phase III study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) in newly diagnosed GBM comparing RT alone (60Gy over six weeks) with RT and concomitant daily temozolomide (75mg/m2/day), followed by adjuvant temozolomide therapy (150–200mg/m2/day for five consecutive days every 28-day cycle, for six cycles).16 The addition of temozolomide to RT increased median survival compared with RT alone (14.6 versus 12.1 months; p<0.0001). Recently, updated results from this study showed that the added survival benefit with temozolomide was maintained, even at five years.25
An established mechanism of temozolomide resistance is based on DNA repair through O-6-methylguanine-DNA methyltransferase (MGMT), an endogenous DNA-repair enzyme that removes alkyl groups from DNA and thus confers resistance to temozolomide and other alkylating agents. MGMT promoter methylation has been shown to predict temozolomide sensitivity in GBM. 6,26 In a companion study to the EORTC/NCIC, tumour specimens were evaluated for methylation status of the MGMT gene promoter. 6 As predicted, the benefit of temozolomide was significantly increased in patients with MGMT promoter methylation. Among GBM patients with MGMT promoter methylation who were treated with temozolomide, median survival was 21.7 months and two-year survival 46%. Temozolomide-treated patients with unmethylated MGMT promoters had a significantly shorter median survival of only 12.7 months and a two-year survival of 13.8%.6 Because this study was conducted retrospectively in a relatively small sample of patients, temozolomide remains the standard of care for newly diagnosed GBM patients, regardless of MGMT promoter methylation status. A randomised phase III trial sponsored by the Radiation Therapy Oncology Group (RTOG 0525) will definitively evaluate the utility of MGMT promoter methylation in determining temozolomide sensitivity. In the future, patients whose tumours have unmethylated MGMT promoters may be offered alternatives to the standard temozolomide regimen. Investigational approaches to overcome MGMT activity include dose-intense temozolomide regimens27,28 or continuous dosing,29 which may deplete the enzyme,30 and combination therapy with O6-benzylguanine or other MGMT inhibitors.31–33
An alternative to systemic chemotherapy involves the surgical implantation of carmustine-containing biodegradable wafers (Gliadel) into the resection cavity following tumour debulking. A double-blind, randomised, phase III trial demonstrated a modest benefit in patients with newly diagnosed GBM. Those patients who received radiation and placebo had a median survival of only 11.6 months compared with 13.9 months for patients who received radiation and carmustine wafers, with median overall survival of 11.6 and 13.9 months, respectively (p=0.03),34 resulting in approval of this therapy by the US Food and Drug Administration (FDA). The benefits of traditional cytotoxic chemotherapy have been modest in the treatment of recurrent GBM. Phase II trials of temozolomide for recurrent GBM demonstrated radiographic response rates (RR) of only 5% and six-month progressionfree survival (PFS6) of about 21%.35,36 However, the recently published RESCUE study showed that continuous dosing of temozolomide at 50mg/m2 daily rather than the conventional 5/28 schedule had favourable efficacy and was well-tolerated as a second-line agent.29 Other agents, such as carmustine, carboplatin, etoposide, irinotecan and procarbazine, lomustine (CCNU) and vincristine (PCV), produce low response rates and no significant survival benefit.37 In selected patients with recurrent GBM who can undergo resection, carmustine implants produce a modest survival advantage of approximately eight weeks.38 In light of the limited data, treatment decisions for patients with recurrent GBM must be made on an individual basis. Factors to consider include tumour histology, prior therapy, time to relapse and performance status. In general, patients with recurrent disease should be enrolled in clinical trials whenever possible.
More recently, clinical trials in recurrent GBM have focused on agents targeting important pathways involved in gliomagenesis and progression. Most notably, angiogenesis inhibitors have changed the treatment of recurrent GBM and will be discussed in greater detail below. Bevacizumab is a monoclonal antibody that selectively binds vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Favourable initial results of bevacizumab in recurrent GBM led to two phase II trials containing bevacizumab monotherapy arms, which demonstrated an RR of 28–35% and PFS6 of 29–42%.39,40 Bevacizumab monotherapy was well-tolerated with a low incidence of intracranial haemorrhage (0–2.4%) and thromboembolism (8.4–12.5%). Based on the results of these trials, bevacizumab was granted accelerated FDA approval in May 2009 for recurrent GBM. Although several phase II studies have demonstrated improved PFS with bevacizumab for recurrent GBM, its impact on overall survival remains unknown.
The previous practice of combining other cytotoxic agents, such as lomustine, carboplatin and etoposide, with bevacizumab for recurrent GBM that progresses despite bevacizumab and irinotecan has recently been challenged by a study that showed that these regimens have marginal efficacy.41 Table 1 summarises the standard therapeutic options for GBM.

Chemotherapy for Anaplastic Glioma

Due to the paucity of randomised clinical trials, there is no consensus in terms of treatment of newly diagnosed anaplastic gliomas (AGs). The recent Randomized Phase III Study of Sequential Radio-chemotherapy of Anaplastic Glioma With PCV or Temozolomide (NOA-04) that randomised patients with AG to initial radiation followed by chemotherapy (temozolomide or PCV) at progression or initial chemotherapy followed by radiation at progression showed no difference in PFS between the two groups, regardless of histology.42 Commonly used adjuvant regimens for anaplastic astrocytoma (AA) following biopsy or surgery include RT with temozolomide (using a similar regimen to GBM) or RT with adjuvant temozolomide only. An ongoing randomised phase III trial of radiation versus radiation plus temozolomide in non-1p/19q co-deleted AG patients may provide further guidance on management of AA.
Tumours with oligodendroglial components, including anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOAs), are less common than AA. However, they have a better prognosis than pure astrocytic tumours and may have increased sensitivity to treatment.43 The majority of AOs and 14–20% of AOAs have deletions of chromosomes 1p and 19q43 due to an unbalanced translocation of 19p to 1q.44 Tumours with 1p/19q co-deletion are particularly sensitive to PCV chemotherapy4,45 and likely have sensitivity to temozolomide, with an increase in response rate from 34 to 59% in one study.26 The value of PCV chemotherapy in combination with RT for newly diagnosed AO/AOA has been evaluated in two large phase III trials.46,47 Although neither study showed an overall survival benefit, patients treated with both RT and PCV chemotherapy had 10–12 months of additional PFS compared with RT alone. As previously mentioned, the NOA-04 trial that randomised AG patients to initial radiation or to initial chemotherapy (PCV or temozolomide) did not demonstrate a difference in PFS, regardless of treatment.42 In all of these studies, 1p/19q co-deletion and MGMT status were associated with marked survival prolongation.
As most published studies in AO/AOA were initiated prior to 2005, the majority of available data involve PCV chemotherapy. Although the NOA-04 study was not powered to directly compare PCV and temozolomide, no PFS difference was observed between patients randomised to initial PCV versus initial temozolomide,42 although temozolomide may be associated with less toxicity than PCV.43 Several large intergroup trials are under way evaluating the optimal combination of RT and temozolomide in patients with newly diagnosed AO/AOA.

Experimental Therapies
Targeted Molecular Therapies

With improved understanding of the pathways that drive gliomagenesis, targeted molecular therapy has emerged as an important treatment paradigm in HGG in the upfront and recurrent setting. Many investigational drugs target signal transduction pathways involved in cell proliferation, growth, survival, adhesion, motility and differentiation.48 Targets of particular importance include receptor tyrosine kinases (RTK) such as vascular endothelial growth factor receptor (VEGFR), integrins, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and cMet. RTKs may be inhibited extracellularly by monoclonal antibodies (mAb) and intracellularly by tyrosine kinase inhibitors (TKIs). Inhibitors of intracellular signalling molecules are also being developed against downstream signalling targets such as phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), Raf and methyl ethyl ketone (MEK). Figure 1 is a schematic of these pathways.

Anti-angiogenic Therapies
Vascular Endothelial Growth Factor Pathway Inhibitors

Angiogenesis is important to the growth and proliferation of HGG and is mediated through several pathways, most notably VEGF.49–51 Higher levels of VEGF expression are observed in more malignant tumours.
Targeting VEGF and VEGFR has been the focus of many recent clinical trials. As noted above, bevacizumab has shown promising activity in recurrent GBM and is now FDA-approved for this indication.40,52,53 Phase II studies of bevacizumab plus irinotecan have also demonstrated efficacy in AG with an RR of 55–66% and PFS6 of 56–61%.54,55 Bevacizumab is generally well-tolerated, with the most common side effects being fatigue, hypertension and proteinuria. Less common serious side effects include thromboembolism, haemorrhage and bowel perforation.
There is emerging evidence that inhibitors of angiogenesis may work synergistically with RT.21 Two large multicentre trials evaluating the efficacy of adding bevacizumab to RT and temozolomide in newly diagnosed GBM patients are under way. Phase II studies of the regimen appear to be safe despite a possible increase in woundhealing complications.56 Treatment of HGG with bevacizumab combined with a variety of targeted molecular agents is being studied as well.52
Another VEGF-pathway inhibitor currently in clinical trials for HGG is aflibercept (a VEGF decoy receptor that consists of a VEGF receptor fused to an immunoglobulin constant region).57 In addition to inhibitors of VEGF such as bevacizumab and aflibercept, there are many small-molecule TKIs directed against VEGFR. Cediranib is an oral pan-VEGFR inhibitor that also has activity against platelet-derived growth factor (PDGFR) and c-Kit. In a phase II clinical trial for recurrent GBM, cediranib achieved a promising RR of 27% and PFS6 of 26%.58 As had been noted in the bevacizumab studies, there was a striking steroid-sparing effect, and the drug was well-tolerated. Other multitargeted VEGFR agents include vandetanib (VEGFR and EGFR), sorafenib (VEGFR, Raf, c-Kit), sunitinib (VEGFR-2, PDFR, c-kit and Flt-3), pazopanib (VEGFR, PDGFR, c-Kit), XL184 (VEGFR and c-Met) and CT322.59
Unfortunately, the benefits of anti-angiogenesis therapy are transitory, and it has been suggested that the impressive radiographic responses observed in patients treated with bevacizumab may be the result of decreased permeability of the vasculature rather than a true antitumour effect (see Figure 2). Mechanisms of resistance to anti-angiogenic therapy are beginning to be elucidated.60,61 Some pre-clinical data suggest that blockade of VEGF-mediated angiogenesis may promote tumour infiltration by co-option of native vessels.62–65 In recurrent HGG patients who are treated with anti-angiogenesis agents, tumour progression is occasionally radiographically observed as an increase in non-enhancing hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) magnetic resonance imaging (MRI). Some hypothesise that this may represent infiltrative tumour growth.66–70
Due to the lack of assessment of non-enhancing tumour and other limitations with the standard Macdonald et al. criteria, the multidisciplinary Response Assessment in Neuro-Oncology (RANO) Working Group recently proposed updated response criteria for HGG.71 In addition, levels of basic fibroblast growth factor (bFGF) and stromal-derived growth factor 1 alpha (SDF-1α) increase in GBM patients when tumours escaped treatment with cediranib.72 These findings imply that one may overcome resistance to anti-angiogenic agents by combining anti-VEGF/VEGFR therapy with agents that target tumour invasion, non-VEGF-pro-angiogenic signalling pathways such as the FGF pathway or vasculogenic pathways such as the SDF-1α pathway.


The αvβ3 and αvβ5 integrins are cell-surface receptors that promote endothelial cell migration and survival during angiogenesis.73 Cilengitide (EMD121974) competitively inhibits αvβ3 and αvβ5. Phase II trials showed a PFS6 of 15% and a median OS of 9.9 months when cilengitide was added to RT and temozolomide. Patients with methylated MGMT promoter had better responses.74 Based on the favourable results of this trial, a multicentre phase III trial is under way using cilengitide in patients with newly diagnosed GBM with methylated MGMT promoter.

Receptor Tyrosine Kinases
Epidermal Growth Factor Receptor Inhibitors

EGFR is the most commonly altered RTK in HGG.75 Approximately 20–30% of GBM have a constitutively active EGFR mutant known as EGFRvIII, and all of these EGFRvIII-expressing tumours also exhibit EGFR amplification or overexpression.76 Signalling through these and other growth factor receptors activates fundamental signal transduction pathways such as the Ras/mitogen-activated protein kinase (MAPK) pathway and the PI3K/Akt/mTOR pathway, both of which promote cell proliferation.10 Additionally, many of these pathways upregulate VEGF.49,77
While subsets of GBM patients have sustained responses to reversible TKIs that target EGFR, to date the studies have been largely disappointing. Studies of erlotinib (EGFR), gefitinib (EGFR) and lapatinib (ErbB2/HER2, EGFR) have failed to demonstrate any significant survival benefit compared with historical controls.78–86 The combination of EGFR inhibitors with other therapies is discussed later in this article.
Potential reasons for lack of response include poor blood–brain barrier penetration, insufficient local tumour concentrations, coactivation of multiple TKIs,87 redundant signalling pathways and resistance. Irreversible EGFR inhibitors, such as BIBW 2992 and PF-00299804, could have better efficacy in GBM than gefitinib or erlotinib due to increased potency and better brain concentration. This newer class of EGFR inhibitors has been shown to circumvent mechanisms of response to gefitinib or erlotinib in non-small-cell lung cancer cells.88–93
mAb and vaccines that target EGFR are currently under investigation in GBM. Both nimotuzumab and cetuximab, a chimeric anti-EGFR human–mouse mAb, are now being studied in combination with RT and temozolomide as upfront GBM therapies. Preliminary results from a phase II clinical trial suggest that the addition of CDX-110, a peptide-based EGFRvIII vaccine, to standard therapy prolongs survival in patients with newly diagnosed GBM.94 However, since patients were required to have gross total resections and EGFRvIII mutation in order to be eligible for the trial, they represent a highly selected group with good prognosis.

Platelet-derived Growth Factor

Platelet-derived growth factors (PDGF) are a pleiotropic family of peptides that signal through PDGFR to stimulate cellular functions including growth, proliferation and differentiation.95 Imatinib mesylate (Gleevec), an inhibitor of PDGFR-α and β, Bcr-Abl, c-Fms and c-Kit tyrosine kinases, demonstrated activity in pre-clinical models of glioma.96 However, in clinical trials neither imatinib monotherapy97,98 nor imatinib in combination with hydroxyurea (a ribonucleoside diphosphate reductase inhibitor)99 has demonstrated clinically useful activity in GBM. One explanation for the lack of efficacy is that imatinib is a substrate for the P-glycoprotein efflux pump that limits its intracranial distribution.100 Tandutinib and dasatinib, second-generation PDGFR inhibitors with improved CNS penetration, are in clinical trials for recurrent HGG.


Scatter factor/hepatocyte growth factor (SF/HGF) and its TKR c-Met play a role in cell growth, cell motility, morphogenesis and angiogenesis.101 AMG 102 is a fully human monoclonal antibody that selectively targets SF/HGF. A phase II study of AMG 102 in recurrent GBM was recently completed but failed to produce any benefit.102 A recent study suggests that the combination of EGFR inhibitors and c-Met inhibitors may be more effective than either agent alone in phosphatase and tensin homologue (PTEN) null GBM.103 Trials of c-Met TKIs such as XL184 are under way in GBM.

Intracellular Signalling Kinases

As activation of several RTKs, including EGFR and PDGFR, converges at the Ras/MAPK and PI3K/Akt pathways, inhibiting these downstream molecules may be more efficacious than targeting individual RTKs.
In the Ras/MAPK pathway, potential targets include Raf, MEK and farnesyltransferase. An early step in activation of the Ras/MAPK pathway is localisation of Ras to the cell membrane, which depends on Ras farnesylation by the enzyme farnesyltransferase. Farnesyltransferase inhibitors (FTI) such as tipifarnib104 showed modest activity as monotherapy in recurrent HGG and are now being studied in combination with temozolomide for HGG.
The Raf serine/threonine kinases are the main downstream effectors of Ras in the MAPK pathway. Sorafenib is an inhibitor of c-Raf kinase, but also inhibits pro-angiogenic RTKs including VEGFR-2, VGFRR-3, PDGFR-β, Flt-3, c-Kit and FGFR-1. Several trials of sorafenib in high-grade glioma are under way, although the preliminary results have been disappointing.
Several PI3K and Akt inhibitors are in development or early clinical trials. XL765, an inhibitor of PI3K and mTOR, is currently in a phase I clinical trial in combination with temozolomide for HGG. Studies of XL147 and BKM120 are planned. Akt inhibitors undergoing evaluation in HGG include perifosine and MK2206.
mTOR, a downstream molecule in the PI3K/Akt pathway, is also an attractive target for therapy.105 The mTOR inhibitor sirolimus (rapamycin) and its analogues temsirolimus, everolimus and ridaforolimus are the most clinically advanced PI3K/Akt pathway inhibitors. Despite promising results from pre-clinical studies, temsirolimus monotherapy was not clinically active in recurrent GBM in two multicentre phase II clinical trials,106,107 possibly because inhibition of only the TORC1 component may result in the activation of Akt. An Akt inhibitor, such as perifosine or MK2206, or a combined PI3K/mTOR inhibitor, such as XL765, may ultimately prove more effective. Studies combining mTOR inhibitors with other targeted agents are discussed below.

New Molecular Targets
Histone Deacetylases

Histone deacetylase (HDAC) inhibitors cause the growth arrest, differentiation or apoptosis of many transformed cells by altering transcription of various genes.108 Vorinostat is a small-molecule inhibitor of most human class I and class II HDACs. Vorinostat demonstrated moderate clinical activity in a phase II study of patients with recurrent GBM with a PFS6 of 15.2%.109 The Adult Brain Tumour Consortium and the North Central Cancer Treatment Group are now jointly conducting a trial of vorinostat with RT and temozolomide in patients with newly diagnosed HGG. Clinical trials combining HDAC inhibitors with other agents such as bortezomib, a proteosome inhibitor, or bevacizumab are currently under way in recurrent GBM. A more potent HDAC inhibitor, LBH589, is entering phase II studies in recurrent GBM.

DNA Repair

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA breaks and facilitates DNA repair by engaging mechanisms such as base excision repair (BER).110 As PARP inhibitors disrupt BER, an important mediator of TMZ resistance, these agents may enhance the antitumour effects of temozolomide against HGG. Two PARP inhibitors, BSI-201 and ABT-888, are being tested in combination with radiation and temozolomide for newly diagnosed GBM.

Glioma Stem Cells

Glioma stem cells (GSCs) are believed to represent a subpopulation of cells in the tumour with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages.111 They may contribute to treatment resistance in HGG.112,113 Stem cells are predicted to be difficult treatment targets because they transition slowly through the cell cycle, express high levels of drug-export proteins and may not express oncoproteins that are targeted by newer chemotherapeutic drugs.112 As a result, there is significant interest in molecular therapies affecting stem-cell pathways, such as notch (e.g. MRK0752 and R4929097), sonic hedgehog (e.g. GDC4409)111,112,114 and hypoxia-inducible factors 1 and 2α.113

Overcoming Resistance to Targeted Molecular Therapy

Monotherapy with most targeted molecular agents (except for anti-VEGFR agents) has shown modest activity at best. These results are not surprising when one considers that most HGG have co-activation of multiple tyrosine kinases87 and highly redundant signalling pathways. Approaches now under evaluation in clinical trials include the combination of a targeted agent with radiotherapy and chemotherapy, the combination of several targeted agents and agents that hit multiple relevant targets at once.10,20,115,116 For example, the EGFR inhibitor erlotinib has been studied in combination with mTOR inhibitors, such as sirolimus117 and temsirolimus.118 Although preliminary results from these erlotinib combination studies suggest only modest efficacy due to poor tolerability,118,119 other combinations may be better tolerated and are in clinical trials. There is also continued interest in clinical trial designs that incorporate tissue specimens to identify biomarkers to predict tumour response to target inhibition.120,121 This may allow identification of patients who are more likely to respond to specific therapies. Advances in molecular profiling of tumour tissue may lead to more selective use of targeted molecular agents and tailoring of therapy to individual patients. A recent study demonstrated that GBM can be subdivided by genomic profiling into four subtypes, each of which demonstrates unique molecular alterations.122
A prominent mechanism of resistance to targeted molecular therapy is inadequate drug delivery across the blood–brain barrier. Increasingly, trials of novel targeted agents include a surgical component to evaluate the ability of the drug to reach therapeutic concentrations in the tumour and inhibit the putative target. Patients with recurrent HGG were administered the agent prior to planned surgery and the tumour is obtained for drug concentration and evidence of pathway inhibition.123 If drug concentration and target inhibition in the tumour is poor, further evaluation of that agent in HGG is probably not warranted.120

Other Therapeutic Modalities

A large number of therapeutic modalities are being explored for HGG. Examples include inhibitors of the ubiquitin-proteosome system such as bortezomib,124–126 heat-shock protein inhibitors,127,128 cytokines,129 gene therapy,130 synthetic chlorotoxins (TM-601),131 chemotherapeutic agents with enhanced ability to penetrate into tumour tissue and convection-enhanced delivery (CED) of drugs and toxins.132 Intracavitary TM-601, the synthetic version of a chlorotoxin found in the venom of the giant yellow Israeli scorpion, is under evaluation in a phase II study. Agents administered directly into HGG via CED that have been studied in phase III clinical trials include interleukin-13 (IL-13), Pseudomonas aeruginosa exotoxin and transferrin-C diphtheriae toxin. Unfortunately, both trials were terminated for futility after interim analysis.133 By contrast, studies of trabedersen (AP1007), a phosphorothioate antisense oligonucleotide against transforming growth factor β2, appears to have activity in recurrent AG and is being evaluated in a phase III study. Therapy involves the insertion or modification of genes in a patient’s cell to treat a disease.134 Transfer of ‘suicidal’ genes via viral vectors such as herpes simple virus thymidine kinase gene (HSV-tk) has demonstrated only limited survival benefit in several clinical trials for recurrent GBM.134
Viral vectors can also deliver pro-apoptotic cytokines such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53 as well as cytokines such as IL-2 and interferon beta (IFN-β). Other methods of delivery under investigation include cell-based transfer and synthetic vectors.
Antitumour vaccines based on peptide antigens, dendritic cells or whole tumour cells represent another major avenue of investigation. Among the many promising vaccines in addition to the previously described CDX-110 are GVAX, which involves administration of irradiated autologous tumour cells mixed with granulocyte macrophage colony-stimulating factor (GM-CSF)-producing cells135 and vaccines against HSP90.136 In small phase II studies, these vaccines appear to be well-tolerated and show promising efficacy compared with historic controls. However, larger prospective controlled studies will be required to confirm any clinical benefit. Table 2 summarises selected novel therapies for HGG.


Despite progress in recent years, the prognosis for most patients with HGG remains poor. The introduction of temozolomide to radiation treatment was an important advance, and anti-angiogenic therapy has now emerged as a critical component of treatment for recurrent tumours. Thus far, the potential of targeted molecular drug therapy has not been fully realised. Future approaches include the use of treatment regimens that inhibit complementary targets, combinations of targeted molecular drugs with RT, chemotherapy and anti-angiogenic therapies and novel agents directed at tumour stem cells. Additionally, the understanding of glioma biology and treatment resistance is evolving at a rapid pace. Genome-wide association studies are just beginning to uncover mutations that will lead to better characterisation of HGG. Therapeutic strategies for circumventing treatment resistance mediated by MGMT and PARP as well as the intrinsic resistance of glioma stem cells are beginning to be developed. ■

Article Information:

Ryan T Merrell and Eudocia C Quant have no conflicts of interest to declare. Patrick Y Wen has received research support from Amgen, Novartis, AstraZeneca, Exelixis, Boehringer-Ingelheim and Schering-Plough and is a member of advisory boards for Esai, Angiochem and Genentech.


Patrick Y Wen, Center for Neuro-oncology, Dana Farber/Brigham and Women’s Cancer Center, SW430, 44 Binney Street, Boston, MA 02115, US. E:




  1. CBTRUS, Central Brain Tumour Registry of the United States, 2008.
  2. Louis DN, et al., The 2007 WHO classification of tumours of the central nervous system, Lyon, France: IARC Press; 2007.
  3. Wen PY, et al., N Engl J Med, 2008;359(5):492–507.
  4. Ino Y, et al., Clin Cancer Res, 2001;7(4):839–45.
  5. Colman H, et al., Arch Neurol, 2008;65(7):877–83.
  6. Hegi ME, et al., N Engl J Med, 2005;352(10):997–1003.
  7. Phillips HS, et al., Cancer Cell, 2006;9(3):157–73.
  8. Mclendon R, et al., Nature, 2008;455(7216):1061–8.
  9. Parsons DW, et al., Science, 2008;321(5897):1807–12.
  10. Furnari FB, et al., Genes Dev, 2007;21(21):2683–2710.
  11. Keles GE, et al., J Neurosurg, 2004;100:41–6.
  12. Sanai N, et al., Neurosurgery, 2008;62(4): 753–64, discussion 264–6.
  13. Stummer W, et al., Neurosurgery, 2008;62(3):564–76.
  14. Lacroix M, et al., J Neurosurg, 2001;95(2):190–98.
  15. Walker MD, et al., J Neurosurg, 1978;49(3):333–43.
  16. Stupp R, et al., N Engl J Med, 2005;352(10):987–96.
  17. Lee SW, et al., Int J Radiat Oncol Biol Phys, 1999;43(1):79–88.
  18. Fiveash JB, et al., Cancer J, 2003;9:222–9.
  19. Stupp R, et al., J Clin Oncol, 2007;25(26): 4127–36.
  20. Chi AS, et al., Expert Opin Ther Targets, 2007;11(4):473–96.
  21. Duda DG, et al., J Clin Oncol, 2007; 25(26):4033–42.
  22. Stieber VW, et al., Neurol Clin, 2007;25(4):1005–33.
  23. Tsao MN, et al., Int J Radiat Oncol Biol Phys, 2005;63(1): 47–55.
  24. Combs SE, et al., J Clin Oncol, 2005;23(34):8863–9.
  25. Stupp R, et al., Lancet Oncol, 2009;10(5):459–66.
  26. Brandes AA, et al., J Clin Oncol, 2006;24(29):4746–53.
  27. Brandes A, et al., Br J Cancer, 2006;95(9):1155–60.
  28. Wick A, et al., J Clin Oncol, 2007;25(22):3357–61.
  29. Perry JR, et al., J Clin Oncol, 28(12):2051–7.
  30. Tolcher AW, et al., Br J Cancer, 2003;88(7):1004–11.
  31. Broniscer A, et al., Clin Cancer Res, 2007;13(22 Pt 1): 6712–18.
  32. Quinn JA, et al., Cancer, 2009;115(13):2964–70.
  33. Quinn JA, et al., J Clin Oncol, 2009;27(8):1262–7.
  34. Westphal M, et al., Neuro Oncol, 2003;5(2):79–88.
  35. Brandes AA, et al., Ann Oncol, 2001;12(2): 255–7.
  36. Yung W, et al., Br J Cancer, 2000;83(5):588–93.
  37. Wong ET, et al., J Clin Oncol, 1999;17(8): 2572–8.
  38. Brem H, et al., Lancet, 1999;345:1008–12.
  39. Kreisl TN, et al., J Clin Oncol, 2009;27(5):740–45.
  40. Friedman HS, et al., J Clin Oncol, 2009;27(28):4733–40.
  41. Quant EC, et al., Neuro Oncol, 2009;11(5):550–55.
  42. Wick W, et al., J Clin Oncol, 2009;27(35): 5874–80.
  43. van den Bent MJ, Neurol Clin, 2007;25(4):1089–1109.
  44. Jenkins RB, et al., Cancer Res, 2006;66(20):9852–61.
  45. Cairncross JG, et al., J Natl Cancer Inst, 1998;90(19):1473–9.
  46. Cairncross G, et al., J Clin Oncol, 2006;24(18): 2707–14.
  47. van den Bent MJ, et al., J Clin Oncol, 2006;24(18):2715–22.
  48. Van Meir EG HC, et al., CA Cancer J Clin, 2010;60(3):166–93.
  49. Jain RK, et al., Nat Rev Neurosci, 2007;8(8):610–22.
  50. Folkman J, N Engl J Med, 1971;285(21):1182–6.
  51. Folkman J, Ann Rev Med, 2006;57:1–18.
  52. Norden AD, et al., Curr Opin Oncol, 2008;20(6):652–61.
  53. Vredenburgh JJ, et al., J Clin Oncol, 2007;25(30):4722–9.
  54. Vredenburgh JJ, et al., Clin Cancer Res, 2007;13(4):1253–9.
  55. Desjardins A, et al., Clin Cancer Res, 2008;14(21):7068–73.
  56. Lai A, et al., Int J Radiat Oncol Biol Phys, 2008;71(5):1372–80.
  57. Holash J, et al., Proc Natl Acad Sci U S A, 2002;99(17):11393–8.
  58. Batchelor TT, et al., J Clin Oncol, 2010;28(17):2817–23.
  59. Norden AD, et al., Nat Rev Neurol, 2009;5(11):610–20.
  60. Bergers G, et al., Nat Rev Cancer, 2008;8(8):592–603.
  61. Ellis LM, et al., Clin Cancer Res, 2008;14(20):6371–5.
  62. Holash J, et al., Science, 1999;284(5422): 1994–8.
  63. Lamszus K, et al., Acta Neurochir Suppl, 2003;88:169–77.
  64. Rubenstein JL, Kim J, Ozawa T, et al., Neoplasia, 2000;2(4):306–14.
  65. Paez-Ribes M, et al., Cancer Cell, 2009;15(3):220–31.
  66. Norden AD, et al., Neurology, 2008;70(10):779–87.
  67. Iwamoto FM, et al., Neurology, 2009;73(15): 1200–1206.
  68. Zuniga RM, et al., J Neurooncol, 2009;91(3): 329–36.
  69. Gerstner ER, et al., Neuro Oncol, 2010;12(5):466–72.
  70. de Groot J, et al., Neuro Oncol, 2010;12(3):233–42.
  71. Wen PY, et al., J Clin Oncol, 2010;28(11):1963–72.
  72. Batchelor T, et al., Cancer Cell, 2007;11(1):83–95.
  73. Avraamides CJ, et al., Nat Rev Cancer, 2008;8(8):604–17.
  74. Stupp R, et al., Neuro Oncol, 2007;9(4):517.
  75. Maher E, et al., Genes Dev, 2001;15(11):1311–33.
  76. Aldape KD, et al., J Neuropathol Exp Neurol, 2004;63(7):700–707.
  77. Guo P, et al., Am J Pathol, 2003;162(4):1083–93.
  78. Brown PD, et al., J Clin Oncol, 2008;26(34):5603–9.
  79. Chakravarti A, et al., J Clin Oncol, 2006;24:1527.
  80. Franceschi E, et al., Br J Cancer, 2007;96(7):1047–51.
  81. Rich JN, et al., J Clin Oncol, 2004; 22(1):133–42.
  82. Lieberman F, et al., J Clin Oncol, (Meeting Abstracts) 2004;22:1510.
  83. Cloughesy T, et al., J Clin Oncol, (Meeting Abstracts) 2005;23:1507.
  84. Vogelbaum MA, et al., Eur J Cancer, 2005;3(2):135S.
  85. Raizer JJ, et al., Neuro Oncol, 2010;12(1):95–103.
  86. Thiessen B, et al., Cancer Chemother Pharmacol, 2009 (Epub ahead of print).
  87. Stommel JM, et al., Science, 2007;318(5848):287–90.
  88. Greulich H, et al., PLoS Med, 2005;2(11):e313.
  89. Kobayashi S, et al., N Engl J Med, 2005;352(8):786–92.
  90. Kobayashi S, et al., Cancer Res, 2005; 65(16):7096–7101.
  91. Kwak EL, et al., Proc Natl Acad Sci U S A, 2005;102(21):7665–70.
  92. Li D, et al., Oncogene, 2008;27(34): 4702–11.
  93. Shimamura T, et al., Cancer Res, 2006;66(13):6487–91.
  94. Sampson JH, et al., J Clin Oncol, (Meeting Abstracts) 2008;26:2011.
  95. George D, Adv Exp Med Biol, 2003;532:141–51.
  96. Kilic T, et al., Cancer Res, 2000;60: 5143–50.
  97. Wen PY, et al., Clin Cancer Res, 2006;12(16):4899–4907.
  98. Raymond E, et al., J Clin Oncol, 2008;26(28):4659–65.
  99. Dresemann G, et al., Neuro Oncol, (Meeting Abstracts) 2008;10(5):820.
  100. Dai H, et al., J Pharmacol Exp Ther, 2003;304:1085–92.
  101. Matsumoto K, et al., J Biochem, 1996;119(4):591–600.
  102. Reardon DA, et al., J Clin Oncol, 2008;26:2051.
  103. Lal B, et al., Mol Cancer Ther, 2009;8(7):1751–60.
  104. Cloughesy TF, et al., J Clin Oncol, 2006;24(22):3651–6.
  105. Chiang GG, et al., Trends Mol Med, 2007;13(10):433–42.
  106. Chang SM, et al., Invest New Drugs, 2005;23(4):357–61.
  107. Galanis E, et al., J Clin Oncol, 2005;23(23):5294–5304.
  108. Jones PA, et al., Nat Rev Genet, 2002;3(6):415–28.
  109. Galanis E, et al., J Clin Oncol, 2009;27(12):2052–8.
  110. Ma WW, et al., CA Cancer J Clin, 2009;59(2):111–37.
  111. Das S, et al., Nat Clin Pract Neurol, 2008;4(8):427–35.
  112. Stiles CD, et al., Neuron, 2008;58(6):832–46.
  113. Dirks PB, J Clin Oncol, 2008;26(17):2916–24.
  114. Bao S, et al., Nature, 2006;444(7120): 756–60.
  115. Sathornsumetee S, et al., Neurol Clin, 2007;25(4):1111–39.
  116. Wen PY, Expert Rev Anticancer Ther, 2009;9(1):7–10.
  117. Friedman HS, et al., J Clin Oncol, (Meeting Abstracts), 2008;26:2062.
  118. Wen P, et al., Neuro Oncol, (Meeting Abstracts), 2008;10(5):824.
  119. Prados M GM, et al., J Clin Oncol, (Meeting Abstracts), 2009;27:2005.
  120. Chang SM, et al., Neuro Oncol, 2008;10(4):631–42.
  121. Brennan C, et al., PLoS One, 2009;4(11):e7752.
  122. Verhaak RG, et al., Cancer Cell, 2010;17(1): 98–110.
  123. Lassman AB, et al., Clin Cancer Res, 2005;11(21):7841–50.
  124. Kubicek GJ, et al., Int J Radiat Oncol Biol Phys, 2009;74(2):433–9.
  125. Phuphanich S, et al., J Clin Oncol, 2006;24(18S):1567.
  126. Kubicek GJ, et al., Int J Radiat Oncol Biol Phys, 2009;74(2):433–9.
  127. Sauvageot CM, et al., Neuro Oncol, 2009;11(2):109–21.
  128. Garcia-Morales P, et al., Oncogene, 2007;26(51): 7185–93.
  129. Hau P, et al., J Clin Oncol, (Meeting Abstracts), 2007;25:12521.
  130. Fulci G, et al., Expert Opin Biol Ther, 2007;7(2):197–208.
  131. Mamelak A, et al., J Clin Oncol, 2006;24(22):3644–50.
  132. Ferguson S, et al., Curr Drug Deliv, 2007;4(2):169–80.
  133. Press release: Celtic Pharma, 2 February 2009.
  134. Germano IM, et al., J Neurooncol, 2009;93(1):79–87.
  135. Nemunaitis J, et al., Cancer Gene Ther, 2006;13(6):555–62.
  136. Parsa A CC, et al., Neuro Oncol, (Meeting Abstracts), 2008;10(5):841.

Further Resources

Share this Article
Related Content In Neurological Oncology
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72