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Medical Progress

Malignant Gliomas in Adults

Patrick Y. Wen, M.D., and Santosh Kesari, M.D., Ph.D. alignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year.1-3 Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality. Despite optimal treatment, the median survival is only 12 to 15 months for patients with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently, there have been important advances in our understanding of the molecular pathogenesis of malignant gliomas and progress in treating them. This review summarizes the diagnosis and management of these tumors in adults and highlights some areas under investigation.

From the Division of Neuro-Oncology, Department of Neurology, Brigham and Womens Hospital; and the Center for Neuro-Oncology, DanaFarber Cancer Institute both in Boston. Address reprint requests to Dr. Wen at the Center for Neuro- Oncology, DanaFarber/Brigham and Womens Cancer Center, SW430D, 44 Binney St., Boston, MA 02115, or at pwen@partners.org. N Engl J Med 2008;359:492-507.
Copyright 2008 Massachusetts Medical Society.

EPIDEMIOL O GIC FE AT UR E S
The annual incidence of malignant gliomas is approximately 5 cases per 100,000 people.1,2 Each year, more than 14,000 new cases are diagnosed in the United States.1,2 Glioblastomas account for approximately 60 to 70% of malignant gliomas, anaplastic astrocytomas for 10 to 15%, and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas for 10%; less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas account for the rest.1,2 The incidence of these tumors has increased slightly over the past two decades, especially in the elderly,4 primarily as a result of improved diagnostic imaging. Malignant gliomas are 40% more common in men than in women and twice as common in whites as in blacks.2 The median age of patients at the time of diagnosis is 64 years in the case of glioblastomas and 45 years in the case of anaplastic gliomas.2,4 No underlying cause has been identified for the majority of malignant gliomas. The only established risk factor is exposure to ionizing radiation.4 Evidence for an association with head injury, foods containing N-nitroso compounds, occupational risk factors, and exposure to electromagnetic fields is inconclusive.4 Although there has been some concern about an increased risk of gliomas in association with the use of cellular telephones,5 the largest studies have not demonstrated this.4,6,7 There is suggestive evidence of an association between immunologic factors and gliomas. Patients with atopy have a reduced risk of gliomas,8 and patients with glioblastoma who have elevated IgE levels appear to live longer than those with normal levels.9 The importance of these associations is unclear. Gene polymorphisms that affect detoxification, DNA repair, and cell-cycle regulation have also been implicated in the development of gliomas.4 Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the LiFraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcots syndrome (intestinal polyposis and brain tumors).10 However, most familial cases have
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no identified genetic cause. Recently, an interna- and 3).18,22 Glioblastomas can be separated into tional consortium, GLIOGENE, was established two main subtypes on the basis of biologic and to study the genetic basis of familial gliomas.11 genetic differences.18,22 Primary glioblastomas typically occur in patients older than 50 years of age and are characterized by EGFR amplification and PATHOL O GIC A L FE AT UR E S mutations, loss of heterozygosity of chromosome Malignant gliomas are histologically heteroge- 10q, deletion of the phosphatase and tensin honeous and invasive tumors that are derived from mologue on chromosome 10 (PTEN), and p16 deglia. The World Health Organization (WHO) clas- letion. Secondary glioblastomas are manifested in sifies astrocytomas on the basis of histologic fea- younger patients as low-grade or anaplastic astrotures into four prognostic grades: grade I (pilo- cytomas and transform over a period of several cytic astrocytoma), grade II (diffuse astrocytoma), years into glioblastomas. These tumors, which are grade III (anaplastic astrocytoma), and grade IV much less common than primary glioblastomas, (glioblastoma).1 Grade III and IV tumors are con- are characterized by mutations in the p53 tumorsidered malignant gliomas. Anaplastic astrocy- suppressor gene,23 overexpression of the platelettomas are characterized by increased cellularity, derived growth factor receptor (PDGFR), abnornuclear atypia, and mitotic activity. Glioblastomas malities in the p16 and retinoblastoma (Rb) also contain areas of microvascular proliferation, pathways, and loss of heterozygosity of chromonecrosis, or both (Fig. 1 and 2). Uncommon glio- some 10q.18,24 Secondary glioblastomas have tranblastoma variants include gliosarcomas, which scriptional patterns and aberrations in the DNA contain a prominent sarcomatous element; giant- copy number that differ markedly from those of cell glioblastomas, which have multinucleated primary glioblastomas.18,22 Despite their genetic giant cells; small-cell glioblastomas, which are differences, primary and secondary glioblastomas associated with amplification of the epidermal are morphologically indistinguishable and respond growth factor receptor (EGFR); and glioblasto- similarly to conventional therapy, but they may remas with oligodendroglial features, which may be spond differently to targeted molecular therapies. associated with a better prognosis than standard High-grade oligodendrogliomas are characterglioblastomas.1,12 Oligodendrogliomas are divided ized by the loss of chromosomes 1p and 19q (in by the WHO into two grades: well-differentiated 50 to 90% of patients).1 Progression from lowoligodendrogli omas and oligoastrocytomas (WHO grade to anaplastic oligodendroglioma is associgrade II), and anaplastic oligodendrogliomas and ated with defects in PTEN, Rb, p53, and cellanaplastic oligoastrocytomas (WHO grade III) cycle pathways.1 (Fig. 1). All of these tumors may contain perinuclear halos (Fig. 2C) and a delicate network of Deregulated Growth Factor Signaling branching blood vessels (chicken-wire pattern).1 The most common defects in growth-factor sigMalignant gliomas typically contain both neo- naling involve EGFR and PDGFR (Fig. 3).18 Amplastic and stromal tissues, which contribute to plification of EGFR occurs almost exclusively in their histologic heterogeneity and variable out- primary glioblastomas and is seen in approximatecome. Molecular studies such as gene-expression ly 40 to 50% of patients with that type of tumor. profiling potentially allow for better classification About half of the tumors with EGFR amplificaof these tumors and separation of the tumors tion express a constitutively autophosphorylated into different prognostic groups.13-17 variant of EGFR, known as EGFRvIII, that lacks the extracellular ligand-binding domain (exons 2 through 7).14,18 This characteristic variant has MOL ECUL A R PATHO GENE SIS become an important therapeutic target for kiRecently, there has been important progress in our nase inhibitors, immunotoxins, and peptide vac understanding of the molecular pathogenesis of cines.3,18 Recently, activating mutations in the exmalignant gliomas, and especially the importance tracellular domain of EGFR have been identified.25 of cancer stem cells.18,19 Malignant transforma- PDGF signaling is a key regulator of glial devel tion in gliomas results from the sequential accu- opment,26 and both ligand and receptors are fremulation of genetic aberrations and the deregu- quently expressed in gliomas, creating an autolation of growth-factor signaling pathways (Fig. 1 crine loop that stimulates proliferation of the
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Cell-of-Origin: Differentiated Glial or Stem or Progenitor Cells

Olig2 expression (100%) P53 mutated (>65%) PDGFA/PDGFR- overexpressed (~60%) Olig2 expression (100%) Olig2 expression (100%) EGFR amplified (~40%) LOH 1p, 4q, 19q EGFR overexpressed (~60%) EGFR overexpressed EGFR mutated (~2030%) PDGF/PDGFR overexpressed MDM2 amplified (~10%) MDM2 overexpressed (>50%) Low-Grade Oligodendroglioma (510 yr)* LOH 10q (~70%) (WHO Grade II) P16Ink4a/P14ARF loss (~30%) P16Ink4a/P14ARF loss PTEN mutated (~40%) RB mutated (~65%) PI3K mutated/amplified (~20%) p53 mutated RB mutated PTEN loss VEGF overexpressed LOH 9p, 10q CDK4/EGFR/MYC amplified VEGF overexpressed

Low-Grade Astrocytoma (510 yr)* (WHO Grade II)

LOH 19q (~50%) RB mutated (~25%) CDK4 amplified (15%) MDM2 overexpressed (10%) P16Ink4a/P14ARF loss (4%) LOH 11p (~30%)

Anaplastic Astrocytoma (23 yr)* (WHO Grade III)

LOH 10q (~70%) DCC loss (~50%) PDGFR- amplified (~10%) PTEN mutated (~10%) PI3K mutated/amplified (~10%) VEGF overexpressed

Anaplastic Oligodendroglioma (35 yr)* (WHO Grade III)

Secondary Glioblastoma (1215 mo)* (WHO Grade IV)

Primary Glioblastoma (1215 mo)* (WHO Grade IV)

Figure 1. Pathways in the Development of Malignant Gliomas. 1st RETAKE AUTHOR: Wen ICM Genetic and chromosomal alterations involved in the development of the three main types of malignant gliomas (primary and secondary 2nd FIGURE: 1 of 5 REG F are glioblastomas and anaplastic oligodendroglioma) shown. Oligodendrocyte transcription factor 2 (Olig2) (blue) and vascular endo 3rd CASE in all high-grade gliomas. Median lengths thelial growth factor (VEGF ) (red) are expressed Revised of survival (asterisks) are shown. A slash 4-C EGFR epidermal indicates one or the other or both. DCC denotes carcinoma, growth factor receptor, LOH loss of EMaildeleted in colorectalLine SIZE ARTIST: ts H/T heterozygosity, MDM2 murine double minuteEnon 2, PDGF platelet-derived growth H/T factor, PDGFR platelet-derived growth factor receptor, Combo 39p6 PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma.
AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

JOB: 35905 tumor.18 Growth factorreceptor signaling, through intermediate signal-transduction generators, results in the activation of transcriptional programs for survival, proliferation, invasion, and angiogenesis. Common signal-transduction pathways activated by these growth factors are the Ras mitogen-activated protein (MAP) kinase pathway, which is involved in proliferation and cellcycle progression, and the phosphatidylinositol 3-kinase (PI3K)Aktmammalian target of rapa mycin (mTOR) pathways, which are involved in the inhibition of apoptosis and cellular proliferation (Fig. 3).18 PTEN, a tumor-suppressor gene that negatively regulates the PI3K pathway, is inactivated in 40 to 50% of patients with glio blastomas.18,27 Many of the above pathways lead to the upregulation of vascular endothelial growth factor (VEGF) and angiogenesis.28,29 EGFR, PDGFR, and VEGF-receptor (VEGFR) pathways also play an

ISSUE: 7-31-08 important role in the normal development of the nervous system by promoting the proliferation of multipotent stem cells. Other developmental pathways that contribute to the biologic features of gliomas are those involving sonic hedgehog, wingless, Notch, CXC chemokine receptor 4 (CXCR4), and bone morphogenetic proteins.19 In addition, oligodendrocyte transcription factor 2 (Olig2), a developmentally regulated, lineage-restricted neural transcription factor, is a universal marker of diffuse gliomas and stem cells that may be a prerequisite for early transformation.30 Drugs that target these pathways are under active investigation as treatment for gliomas.

Role of Stem Cells in Pathogenesis and Resistance to Therapy

Although the genetic and signaling pathways involved in the development of malignant gliomas

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* *
C D

Figure 2. Pathological Features of Malignant Gliomas. Panels A and B show the histologic appearance of a glioblastoma, characterized by nuclear pleomorphism, dense cellularity, and pseudopalisading necrosis (asterisk) (Panel A, hematoxylin and eosin) as well as vascular endothelial prolifera1st D show the histologic features wen AUTHOR ICM (Panel tion (asterisk) and mitotic figures (arrows) B, hematoxylin and eosin).RETAKE Panels C and REG F FIGURE 2a-f of an anaplastic oligodendroglioma, including the typical perinuclear halo (fried egg)2nd appearance (Panel C, hematoxy3rd CASE lin and eosin) and diffuse Olig2 staining (Panel D, brown color). The proliferation index can be quantified by immunohisTITLE Revised EMail tochemical analysis with the use of Ki67 staining (Panel E, black color), 4-C and heterogeneous EGFR amplification by coloriLine SIZE Enon than ARTIST: mst (brown metric in situ hybridization showing more two signals in nuclei) in almost all tumor cells (Panel F). H/T spots H/T FILL 33p9 Combo (Courtesy of Ali G. Saad, M.D., Department of Pathology, Brigham and Womens Hospital.)
AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully.

have been relatively well characterized, the celluJOB: 35905 lar origins of these tumors are unknown. The adult nervous system harbors neural stem cells that are capable of self-renewal, proliferation, and

differentiation into distinctive mature cell types.31 ISSUE: 7-31-08 There is increasing evidence that neural stem cells, or related progenitor cells, can be transformed into cancer stem cells and give rise to malignant gliomas
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by escaping the mechanisms that control proliferation and programmed differentiation (Fig. 4).32-36 These stem cells are identified by several immunocytochemical markers, such as CD133, a glycoprotein also known as prominin 1.26,32,35,37 Although stem cells account for only a minority of the cells within malignant gliomas, they appear to be critical for generating these tumors.36,38 Recent studies suggest that glioma stem cells produce VEGF and promote angiogenesis in the tumor microenvironment.39 In addition, tumor stem cells appear to require a vascular niche for optimal function.40 These observations raise the possibility that antiangiogenic therapy may inhibit the functioning of glioma stem cells. There is growing evidence that glioma stem cells may contribute to the resistance of malignant gliomas to standard treatments (Fig. 4). Radioresistance in stem cells generally results from the preferential activation of DNA-damageresponse pathways,41 whereas chemoresistance results partly from the overexpression of O6-meth ylguanineDNA methyltransferase (MGMT), the up-regulation of multidrug resistance genes, and the inhibition of apoptosis.42-44 Therapeutic strategies that effectively target stem cells and overcome their resistance to treatment will be necessary if malignant gliomas are to be completely eradicated (Fig. 4). A better understanding of the biologic differences between normal and cancer stem cells will be required to develop selective therapies that spare normal brain cells.

DI AGNOSIS
Clinical Presentation

Patients with malignant gliomas may present with a variety of symptoms, including headaches, seizures, focal neurologic deficits, confusion, memory loss, and personality changes. Although the classic headaches that are suggestive of increased intracranial pressure are most severe in the morning and may wake the patient from sleep, many patients experience headaches that are indistinguishable from tension headaches. When severe, the headaches may be associated with nausea and vomiting.

Figure 3 (facing page). Major Signaling Pathways in Malignant Gliomas and the Corresponding Targeted Agents in Development for Glioblastoma. RTK inhibitors that target epidermal growth factor (EGF) receptor include gefitinib, erlotinib, lapatinib, BIBW2992, and vandetanib; those that target plateletderived growth factor (PDGF) receptor include imatinib, dasatinib, and tandutinib; those that target vascular endothelial growth factor (VEGF) receptor include cediranib, pazopanib, sorafenib, sunitinib, vatalanib, vandetanib, and XL184. EGF receptor antibodies include cetuximab and panitumumab. Farnesyl transferase inhibitors include lonafarnib and tipifarnib; HDAC inhibitors include depsipeptide, vorinostat, and LBH589; PI3K inhibitors include BEZ235 and XL765; mTOR inhibitors include sirolimus, temsirolimus, everolimus, and deforolimus; and VEGF receptor inhibitors include bevacizumab, aflibercept (VEGF-trap), and CT-322. Growth factor ligands include EGF, PDGF, IGF, TGF, HGF/SF, VEGF, and FGF. Stem-cell pathways include SHH, wingless family, and Notch. Akt denotes murine thymoma viral oncogene homologue (also known as protein kinase B), CDK cyclin-dependent kinase, ERK extracellular signal-regulated kinase, FGF fibroblast growth factor, FTI farnesyl transferase inhibitors, GDP guanine diphosphate, Grb 2 growth factor receptor-bound protein 2, GTP guanine triphosphate, HDAC histone deacetylase, HGF/SF hepatocyte growth factor/scatter factor, IGF insulin-like growth factor, MEK mitogen-activated protein kinase kinase, mTOR mammalian target of rapamycin, NF1 neurofibromin 1, PIP2 phosphatidylinositol (4,5) biphosphate, PIP3 phosphatidylinositol 3,4,5-triphosphate, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, PTEN phosphatase and tensin homologue, RAF v-raf 1 murine leukemia viral oncogene homologue 1, RAS rat sarcoma viral oncogene homologue, RTK receptor tyrosine kinase inhibitor, SHH sonic hedgehog, SOS son of sevenless, Src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue, TGF transforming growth factor family, and TSC1 and 2 tuberous sclerosis gene 1 and 2. Red text denotes inhibitors. Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21

typically show a heterogeneously enhancing mass with surrounding edema. Glioblastomas frequently have central areas of necrosis and more extensive peritumoral edema than that associated with anaplastic gliomas.45 Functional MRI may help define the relationship of speech and motor areas to the tumor and aid in the planning of surgery. Diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI to Imaging measure vessel permeability, and perfusion imThe diagnosis of malignant gliomas is usually aging to measure relative cerebral blood volume suggested by magnetic resonance imaging (MRI) are increasingly used as diagnostic aids and as a or computed tomography. These imaging studies means of monitoring the response to therapy.46
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Proton magnetic resonance spectroscopy detects the levels of metabolites and may help differentiate a tumor from necrosis or benign lesions. In patients with malignant gliomas, this imaging technique typically shows an increase in the cho-

line peak (reflecting increased membrane turnover) and a decrease in the N-acetyl aspartate peak (reflecting decreased neuronal cellularity), as compared with the findings in unaffected areas of the brain.45,46 Positron-emission tomography that uses
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Figure 4. Resistance Mechanisms in Glioma Cells. Normal neural stem cells self-renew and give rise to multipotential progenitor cells that form neurons, oligodendroglia, and astrocytes. Glioma stem cells arise from the transformation of either neural stem cells or progenitor cells (red) or, less likely, from differentiation of a oligodendrocytes or astrocytes (thin red arrows) and lead to malignant gliomas. Glioma stem cells are relatively resistant to standard treatments such as radiation and chemotherapy and lead to regrowth of the tumor after treatment. Therapies directed at stem cells can deplete these cells and poten tially lead to more durable tumor regression (blue).

isotopes such as 18F-fluorodeoxyglucose, 18F-fluoro-l-thymidine, 11C-methionine, and 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine is being evaluated for its usefulness in diagnosis and in monitoring the response to therapy.47 In up to 40% of cases, the MRI studies that
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are performed in the first month after radiotherapy show increased enhancement.48 In 50% of these cases, the increased enhancement reflects a transient increase in vessel permeability as a result of radiotherapy, a phenomenon termed pseudoprogression, which improves with time.48 Differen-

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tiating this transient effect from true progres- of 20 to 30%.49,53 The risk of intratumoral hemsion of the cancer can be challenging initially, orrhage associated with anticoagulation therapy even with advanced imaging techniques. in patients with gliomas who have venous thromboembolism is low,49,54 whereas inferior vena cava filters are associated with high complication T R E ATMEN T rates.55 Unless a patient with malignant glioma General Medical Management and venous thromboembolism has an intracereMuch of the care of patients with malignant bral hemorrhage or other contraindications, it is gliomas involves general medical management. generally safe to provide anticoagulation therapy The most common problems include seizures, per- for the venous thromboembolism. Low-molecularitumoral edema, venous thromboembolism, fa- weight heparin may be more effective and safer tigue, and cognitive dysfunction.49 Patients who than warfarin.56 present with seizures should be treated with anPatients with malignant gliomas frequently ex tiepileptic drugs. Since antiepileptic drugs that perience fatigue and may benefit from treatment induce hepatic cytochrome P-450 enzymes, such with modafinil or methylphenidate.57 Methyl as phenytoin and carbamazepine, increase the me- phenidate may also help abulia, and donepezil58 tabolism of many chemotherapeutic agents, anti- and memantine may reduce memory loss, although epileptic drugs that do not induce these enzymes, evidence supporting these approaches remains such as levetiracetam, are generally preferred. The limited. Depression is underdiagnosed in patients use of prophylactic antiepileptic drugs in patients with malignant gliomas, and antidepressants and with malignant gliomas who have never had a psychiatric support are often invaluable.59 seizure is controversial. The American Academy of Neurology issued a practice guideline indicating Specific Therapy for Newly Diagnosed that there is no evidence that prophylactic anti- Malignant Gliomas epileptic drugs are beneficial and advises against The standard therapy for newly diagnosed maligthe routine use of antiepileptic drugs in patients nant gliomas involves surgical resection when feawith brain tumors who have not had seizures.50 sible, radiotherapy, and chemotherapy (Table 1). Corticosteroids such as dexamethasone are fre- Malignant gliomas cannot be completely eliminatquently used to treat peritumoral edema. Cush- ed surgically because of their infiltrative nature, ings syndrome and corticosteroid myopathy may but patients should undergo maximal surgical develop in patients who require prolonged treat- resection whenever possible. Surgical debulking ment with high doses of corticosteroids. Patients reduces the symptoms from mass effect and prowith brain tumors who receive corticosteroids are vides tissue for histologic diagnosis and molecuat increased risk for Pneumocystis jiroveci pneumoni- lar studies. Advances such as MRI-guided neurotis, and prophylactic antibiotic therapy should be navigation, intraoperative MRI, functional MRI, considered,49 although a recent meta-analysis did intraoperative mapping,60 and fluorescence-guidnot show a benefit from this approach.51 As the ed surgery61 have improved the safety of surgery rate of survival among patients with malignant and increased the extent of resection that can be glioma improves, long-term complications from achieved. The value of surgery in prolonging surtreatment with corticosteroids, including osteo- vival is controversial, but patients who undergo porosis and compression fractures, are becoming extensive resection probably have a modest surincreasingly evident, and preventive measures, vival advantage.60-62 Stereotactic biopsies should such as treatment with vitamin D, calcium sup- be performed only in patients who have inoperplements, and bisphosphonates, should be con- able tumors that are located in critical areas. Radiotherapy is the mainstay of treatment for sidered. Novel therapies such as corticotropinreleasing factor, bevacizumab (a humanized VEGF malignant gliomas. The addition of radiotherapy monoclonal antibody), and VEGFR inhibitors de- to surgery increases survival among patients with crease peritumoral edema and may reduce the glioblastomas from a range of 3 to 4 months to a range of 7 to 12 months.63,64 Conventional raneed for corticosteroids.49,52 Patients with malignant gliomas are at in- diotherapy consists of 60 Gy of partial-field extercreased risk for venous thromboembolism from nal-beam irradiation delivered 5 days per week leg and pelvic veins, with a cumulative incidence in fractions of 1.8 to 2.0 Gy. After standard radion engl j med 359;5 www.nejm.org july 31, 2008

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Table 1. Summary of Current Treatments for Malignant Gliomas.* Type of Tumor Newly diagnosed tumors Glioblastomas (WHO grade IV) Anaplastic astrocytomas (WHO grade III) Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas (WHO grade III) Recurrent tumors Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant TMZ or carmustine wafers (Gliadel) Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy, plus concomitant and adjuvant TMZ or adjuvant TMZ alone Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy alone, TMZ or PCV with or without radiotherapy afterward, radiotherapy plus concomitant and adjuvant TMZ, or radiotherapy plus adjuvant TMZ Reoperation in selected patients, carmustine wafers (Gliadel), conventional chemotherapy (e.g., lomustine, carmustine, PCV, carboplatin, irinotecan, etoposide), bevacizumab plus irinotecan, experimental therapies Therapy

* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 PCV denotes procarbazine, lomustine (CCNU), and vincristine, and TMZ temozolomide. Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. Concomitant TMZ is administered at a dose of 75 mg per square meter of body-surface area per day for 42 days with radiotherapy. Beginning 4 weeks after radiotherapy, adjuvant TMZ is administered at a dose of 150 mg per square meter per day on days 1 to 5 of the first 28-day cycle, followed by 200 mg per square meter per day on days 1 to 5 of each subsequent 28-day cycle, if the first cycle was well tolerated. PCV therapy consists of lomustine (CCNU), 110 mg per square meter, on day 1; procarbazine, 60 mg per square meter, on days 8 to 21; and vincristine, 1.5 mg per square meter (maximum dose, 2 mg), on days 8 and 29.

therapy, 90% of the tumors recur at the original site.65 Strategies to increase the radiation dose to 66 and the tumor with the use of brachytherapy 67,68 stereotactic radiosurgery have failed to improve survival. Newer chemotherapeutic agents,69 targeted molecular agents,20 and antiangiogenic agents70 may enhance the effectiveness of radiotherapy. Patients who are older than 70 years of age have a worse prognosis than younger patients and represent a particular challenge. Among these patients, radiotherapy produces a modest benefit in median survival (29.1 weeks) as compared with supportive care (16.9 weeks).71 Since older patients often tolerate radiotherapy less well than younger patients, an abbreviated course of radiotherapy (40 Gy in 15 fractions over a period of 3 weeks)72 or chemotherapy with temozolomide (an oral alkylating agent with good penetration of the bloodbrain barrier) alone73 may be considered, since the outcomes with these approaches are similar to the outcomes with conventional radiotherapy regimens. Chemotherapy is assuming an increasingly important role in the treatment of malignant gliomas. Although early studies of adjuvant chemotherapy for malignant gliomas with the use of nitroso ureas failed to show a benefit,63,74 two metaanalyses have suggested that adjuvant chemother
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apy results in a modest increase in survival (a 6 to 10% increase in the 1-year survival rate).75,76 The European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) conducted a phase III trial comparing radiotherapy alone (60 Gy over a period of 6 weeks) with radiotherapy and concomitant treatment with temozolomide (75 mg per square meter of body-surface area per day for 6 weeks), followed by adjuvant temozolomide therapy (150 to 200 mg per square meter per day for 5 days every 28 days for 6 cycles), in patients with newly diagnosed glioblastomas.64 As reported by Stupp et al., the combination of radiotherapy and temozolomide had an acceptable side-effect profile and, as compared with radiotherapy alone, increased the median survival (14.6 months vs. 12.1 months, P<0.001).64 In addition, the survival rate at 2 years among the patients who received radiotherapy and temozolomide was significantly greater than the rate among the patients who received radiotherapy alone (26.5% vs. 10.4%),64 establishing radiotherapy with concomitant and adjuvant temozolomide as a useful combination for newly diagnosed glioblastomas. MGMT is an important repair enzyme that contributes to resistance to temozolomide. In a companion study to the EORTCNCIC study reported by Stupp et al., tumor specimens from the pa-

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tients were examined for epigenetic silencing of the MGMT gene.15 MGMT promoter methylation silences the gene, thus decreasing DNA repair activity and increasing the susceptibility of the tumor cells to temozolomide. Patients with glioblastoma and MGMT promoter methylation (45% of the total) who were treated with temozolomide had a median survival of 21.7 months and a 2-year survival rate of 46%. In contrast, patients without MGMT promoter methylation who were treated with temozolomide had a significantly shorter median survival of only 12.7 months and a 2-year survival rate of 13.8%.15 Currently, temozolomide is used in the treatment of glioblastomas regardless of MGMT promoter methylation status. However, if the importance of MGMT promoter methylation is confirmed by the results of an ongoing study by the Radiation Therapy Oncology Group (RTOG 0525), patients with unfavorable MGMT methylation status may be selected for other treatments in future investigations. Studies of dose-intensive temozolomide regimens to deplete MGMT and of combinations of temozolomide with inhibitors of MGMT, such as O6-benzylguanine, and inhibitors of other repair enzymes, such as poly-(ADP-ribose)-polymerase, are in progress. Another chemotherapeutic approach involves the implantation of biodegradable polymers containing carmustine (Gliadel Wafers, MGI Pharma) into the tumor bed after resection of the tumor. The aim of treatment with these polymers, which release carmustine gradually over the course of several weeks, is to kill residual tumor cells. In a randomized, placebo-controlled trial that investigated the use of these polymers in patients with newly diagnosed malignant gliomas, median survival increased from 11.6 months to 13.9 months (P=0.03).77 This survival advantage was maintained at 2 and 3 years.78
Therapy for Anaplastic Gliomas

Anaplastic astrocytomas are treated with radiotherapy and either concurrent and adjuvant temozolomide (as for glioblastomas) or adjuvant temozolomide alone. Currently, there are no findings from controlled trials that support the use of concurrent temozolomide in patients with anaplastic astrocytomas. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas are an important subgroup of malignant gliomas that are generally more responsive to therapy than are pure astrocytic tumors.79 A codeletion of chromosomes 1p and

19q,79 mediated by an unbalanced translocation of 19p to 1q,80 occurs in 61 to 89% of patients with anaplastic oligodendrogliomas and 14 to 20% of patients with anaplastic oligoastrocytomas. Tumors in patients with the 1p and 19q codeletion are particularly sensitive to chemotherapy with PCV procarbazine, lomustine (CCNU), and vincristine with response rates of up to 100%, as compared with response rates of 23 to 31% among patients without the deletion of chromosomes 1p and 19q.81,82 The reason for the increased chemosensitivity of tumors in patients with the 1p and 19q codeletion is unclear. One study suggested that 1p loss is associated with decreased levels of stathmin and an increased sensitivity to nitroso ureas.83 The status of chromosomes 1p and 19q, rather than standard histologic assessment, is now used as an eligibility criterion in studies involving patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, reflecting a paradigm shift in the design of clinical trials for patients with these tumors. Two large phase III studies of PCV chemotherapy with radiotherapy, as compared with radiotherapy alone, in patients with newly diagnosed anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, have been reported.84,85 In both studies, the addition of chemotherapy to radiotherapy increased the time to tumor progression by 10 to 12 months but did not improve overall survival (median, 3.4 and 4.9 years).84,85 The failure of chemotherapy to increase survival may be partly explained by the fact that patients who initially received radiotherapy alone subsequently received chemotherapy when they had a relapse, so that most patients in both groups eventually received chemotherapy. In both studies, patients with the codeletion of 1p and 19q had improved survival as compared with those without the codeletion of 1p and 19q. Although most studies involving patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas were conducted with PCV chemotherapy, temozolomide is likely to have similar activity and less toxicity79; however, studies directly comparing the two regimens have not been performed.
Therapy for Recurrent Malignant Gliomas

Despite optimal treatment, nearly all malignant gliomas eventually recur. For glioblastomas, the median time to progression after treatment with radiotherapy and temozolomide is 6.9 months.64 If the tumor is symptomatic from mass effect, re501

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operation may be indicated (Table 1). However, surgery performed in selected patients results in only limited prolongation of survival.86 The usefulness of radiotherapy for recurrent malignant gliomas is controversial.87 Although some reports have suggested that fractionated stereotactic reirradiation88 and stereotactic radiosurgery68 may be beneficial, selection bias may have influenced these results. The value of conventional chemotherapy for recurrent malignant gliomas is modest. In general, chemotherapy is more effective for anaplastic gliomas than for glioblastomas.79,87 Temozolomide was evaluated in a phase II study involving patients with recurrent anaplastic gliomas who had previously been treated with nitrosoureas; the study showed a 35% response rate. The 6-month rate of progression-free survival was 46%,89 comparing favorably with the 31% rate of progressionfree survival at 6 months for therapies that were reported to be ineffective.90 In contrast, temozolomide has only limited activity in patients with recurrent glioblastomas (response rate, 5.4%; 6-month rate of progression-free survival, 21%).91 Other chemotherapeutic agents that are used for recurrent gliomas include nitrosoureas, carboplatin, procarbazine, irinotecan, and etoposide. Carmustine wafers have modest activity, increasing the median survival by approximately 8 weeks in patients with recurrent glioblastomas.92

have poor penetration across the bloodtumor barrier. There has been considerable interest in identifying molecular features of the tumor that predict a response, so that patients who are most likely to benefit can be selected for a particular treatment. EGFR inhibitors appear to be more effective in patients who have tumors with EGFRvIII mutations and intact PTEN than in patients who do not have these molecular changes99; patients who have tumors with increased activity of the PI3KAkt pathway, as indicated by an increase in phosphorylated Akt, generally do not have a response.100 Current experimental strategies to increase the effectiveness of targeted molecular therapies include the use of a single agent targeted against several kinases, combinations of agents that inhibit complementary targets such as EGFR and mTOR (Table 2 and Fig. 5A through 5D), and targeted agents combined with radiotherapy and chemotherapy.3,18,20,21
Antiangiogenic Agents

IN V E S T IG AT IONA L THER A PIE S

Targeted Molecular Therapies

The improved understanding of the molecular pathogenesis of malignant gliomas has allowed a more rational use of targeted molecular therapies (Fig. 3).18,20,21 Particular interest has focused on inhibitors that target receptor tyrosine kinases such as EGFR,93 PDGFR,94 and VEGFR,52 as well as on signal-transduction inhibitors targeting mTOR,95,96 farnesyltransferase,97 and PI3K (Table 2). Single agents have only modest activity, with response rates of 0 to 15% and no prolongation of 6-month progression-free survival.3,20,21 These disappointing results are due to several factors. Most malignant gliomas have coactivation of multiple tyrosine kinases,98 as well as redundant signaling pathways, thus limiting the activity of single agents. In addition, many of these agents

Malignant gliomas are among the most vascular of human tumors,18 making them especially attractive targets for angiogenesis inhibitors.29 Although older antiangiogenic agents such as thalidomide had only modest activity,101 newer and more potent angiogenesis inhibitors show promising activity. In preliminary studies, treatment with the combination of bevacizumab and irinotecan was associated with a low incidence of hemorrhage and response rates of 57 to 63% among patients with malignant gliomas (Fig. 5E through 5H).102,103 Some of the improvement that is seen on radiographic images may be artifactual, caused by reduced vascular permeability and decreased contrast enhancement as a result of the inhibition of VEGF. However, this regimen also has antitumor activity, as evidenced by the fact that it increased the 6-month rate of progression-free survival to 46% among patients with recurrent glioblastomas,102,103 as compared with a 6-month rate of progression-free survival of 21% for patients who were receiving treatment with temozolomide.91 Recently, a large, randomized phase II trial of bevacizumab alone and bevacizumab with irinotecan was completed. Preliminary results confirmed the safety of bevacizumab and showed an increase in the 6-month rate of progression-free survival to 35.1% for patients receiving bevacizu

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Table 2. Selected Investigational Treatments for Malignant Gliomas.* Type of Treatment Convection-enhanced surgical delivery of pharmacologic agent Drugs to overcome resistance to TMZ Dose-dense TMZ MGMT inhibitors PARP inhibitors New chemotherapies Antiangiogenic therapies Anti-v5 integrins Anti-hepatocyte growth factor Anti-VEGF Anti-VEGFR Other agents Targeted molecular therapies Akt EGFR inhibitors FTI inhibitors HDAC inhibitors HSP90 inhibitors Met mTOR inhibitors PI3K inhibitors PKC PDGFR inhibitors Proteasome Raf Src TGF- Combination therapies Perifosine Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab, cetuximab Tipifarnib, lonafarnib Vorinostat, depsipeptide, LBH589 ATI3387 XL184 Everolimus, sirolimus, temsirolimus, deforolimus BEZ235, XL765 Enzastaurin Dasatinib, imatinib, tandutinib Bortezomib Sorafenib Dasatinib AP12009 Erlotinib plus temsirolimus, gefitinib plus everolimus, gefitinib plus sirolimus, sorafenib plus temsirolimus, erlotinib, or tipifarnib, pazopanib plus lapatinib DCVax, CDX-110
131I-anti-tenascin

Example Cintredekin besudotox

O6-benzylguanine BSI-201, ABT-888 RTA744, ANG1005 Cilengitide AMG-102 Bevacizumab, aflibercept (VEGF-Trap) Cediranib, pazopanib sorafenib, sunitinib, vandetinib, vatalanib, XL184, CT-322 Thalidomide

Immunotherapies Dendritic cell and EGFRvIII peptide vaccines Monoclonal antibodies Gene therapy Other therapies
131I-TM-601

antibody

* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 EGFR denotes epidermal growth factor receptor, FTI farnesyltransferase, HDAC histone deacetylase, HSP90 heat-shock protein 90, MGMT O6-methylguanineDNA methyltransferase, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose) polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PKC protein kinase C , TGF transforming growth factor, TMZ temozolomide, and VEGFR vascular endothelial growth factor receptor.

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Figure 5. MRI Scans Showing Responses to Targeted Agents. Panels A through D show MRI scans in a patient with a recurrent malignant glioma who was treated with a combination of erlotinib (an inhibitor of epidermal growth factor receptor [EGFR]) and sirolimus (an inhibitor of the mamRETAKE 1st wen obtained after the AUTHOR ICM malian target of rapamycin [mTOR]). T1-weighted images administration of gadolinium show a reREG F FIGURE duction in the size of the enhancing tumor from the 5a-h pretreatment image (Panel A) 2nd to the image obtained 2 months 3rd CASE TITLE inversion recovery (FLAIR) Revised after treatment (Panel B), with fluid-attenuated studies showing a reduction of edema EMail from the pretreatment image (Panel C) to the post-treatment image4-C (Panel D). Panels E through H show MRI scans Line SIZE Enon who ARTIST: mst with H/T H/T of a recurrent glioblastoma in a patient was treated a combination of bevacizumab and irinotecan. T1FILL 33p9 Combo weighted images obtained after the administration of gadolinium show a reduction in the size of the enhancing tuNOTE: obtained 7 months after treatment (Panel F) mor from the image obtained before treatment AUTHOR, (Panel E)PLEASE to the image redrawn and type has been (Panel reset. G) to the post-treatment FLAIR and an associated reduction of edemaFigure from has thebeen pretreatment FLAIR image Please check carefully. image (Panel H).
JOB: 35905 ISSUE: 7-31-08

mab alone and 50.2% for patients receiving the combination of bevacizumab and irinotecan.104 A phase II trial of the pan-VEGFR inhibitor ce dira nib in patients with recurrent glioblastomas showed response rates in excess of 50% and prolongation of the 6-month rate of progression-free survival to approximately 26%.52 These agents also decrease peritumoral edema, potentially allowing for a reduction in corticosteroid requirements. Since antiangiogenic agents may have synergistic activity with radiotherapy, there is increasing interest in combining them with radiotherapy and temozolomide in patients with newly diagnosed glioblastomas.29,70 As noted previously, glioma stem cells produce VEGF39 and require a vascular niche for optimal function.40 Antiangiogenic agents may therefore also target glioma stem cells.

cross the bloodtumor barrier more effectively, gene therapy,105 peptide and dendritic-cell vac cines,106 radiolabeled monoclonal antibodies against the extracellular matrix protein tena scin,107 synthetic chlorotoxins (131I-TM-601),108 and infusion of radiolabeled drugs and target ed toxins into the tumor and surrounding brain by means of convection-enhanced delivery (Table 2).109

PRO GNOS T IC FAC T OR S

The most important adverse prognostic factors in patients with malignant gliomas are advanced age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor.110 There are ongoing efforts to identify biologic and genetic alterations in the tumors that Other Therapies may provide additional prognostic information, as Other investigational therapies for malignant well as guidance in making decisions about optigliomas include chemotherapeutic agents that mal therapy.15,16,82
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Supported by grants from the National Institutes of Health (U01 CA062407, to Dr. Wen; and KO8 CA1240804, to Dr. Kesari), a Sontag Foundation Distinguished Scientist Grant (to Dr. Kesari), and research support from the Elizabeth Atkins and Will Kraft Brain Tumor Research Funds (to Dr. Wen) and the John Kenney Brain Tumor Research Fund (to Dr. Kesari). Dr. Wen reports receiving speaking fees from ScheringPlough, serving as a consultant for AngioChem, and receiving research funding from Exelixis, Schering-Plough, Genentech, GlaxoSmithKline, Amgen, AstraZeneca, and Celgene. Dr. Kesari reports receiving consulting fees from BristolMyers Squibb, speaking fees from Enzon, and research funding from Adnexus. No other potential conflict of interest relevant to this article was reported. We thank Drs. Andrew Norden and Elizabeth Claus for helpful comments. This article is dedicated to the memories of Elizabeth Atkins, Will Kraft, and John Kenney.

SUM M A R Y
Recently, there has been important progress in the treatment of malignant gliomas111 and in our understanding of the molecular pathogenesis of these tumors and the critical role that stem cells play in their development and resistance to treatment. As our understanding of the molecular correlates of response improves, it may be possible to select the most appropriate therapies on the basis of the patients tumor genotype. These advances provide real opportunities for the development of effective therapies for malignant gliomas.
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