malignant gliomas in adult

review article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;5 www.nejm.org july 31, 2008492

Medical Progress

Malignant Gliomas in AdultsPatrick Y. Wen, M.D., and Santosh Kesari, M.D., Ph.D.

From the Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital; and the Center for Neuro-Oncology, Dana−Farber Cancer In-stitute — both in Boston. Address reprint requests to Dr. Wen at the Center for Neuro- Oncology, Dana−Farber/Brigham and Women’s Cancer Center, SW430D, 44 Binney St., Boston, MA 02115, or at [email protected].

N Engl J Med 2008;359:492-507.Copyright © 2008 Massachusetts Medical Society.

Malignant 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, malig-

nant 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 patho-genesis of malignant gliomas and progress in treating them. This review summa-rizes the diagnosis and management of these tumors in adults and highlights some areas under investigation.

EPIDEMIOL O GIC FE AT UR ES

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 glioblasto-ma 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 Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syn-drome (intestinal polyposis and brain tumors).10 However, most familial cases have

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n engl j med 359;5 www.nejm.org july 31, 2008 493

no identified genetic cause. Recently, an interna-tional consortium, GLIOGENE, was established to study the genetic basis of familial gliomas.11

PATHOL O GIC A L FE AT UR ES

Malignant gliomas are histologically heteroge-neous and invasive tumors that are derived from glia. The World Health Organization (WHO) clas-sifies astrocytomas on the basis of histologic fea-tures into four prognostic grades: grade I (pilo-cytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma).1 Grade III and IV tumors are con-sidered malignant gliomas. Anaplastic astrocy-tomas are characterized by increased cellularity, nuclear atypia, and mitotic activity. Glioblastomas also contain areas of microvascular proliferation, necrosis, or both (Fig. 1 and 2). Uncommon glio-blastoma variants include gliosarcomas, which contain a prominent sarcomatous element; giant-cell glioblastomas, which have multinucleated giant cells; small-cell glioblastomas, which are associated with amplification of the epidermal growth factor receptor (EGFR); and glioblasto-mas with oligodendroglial features, which may be associated with a better prognosis than standard glioblastomas.1,12 Oligodendrogliomas are divided by the WHO into two grades: well-differentiated oligodendrogli omas and oligoastrocytomas (WHO grade II), and anaplastic oligodendrogliomas and anaplastic oligoastrocytomas (WHO grade III) (Fig. 1). All of these tumors may contain perinu-clear halos (Fig. 2C) and a delicate network of branching blood vessels (chicken-wire pattern).1

Malignant gliomas typically contain both neo-plastic and stromal tissues, which contribute to their histologic heterogeneity and variable out-come. Molecular studies such as gene-expression profiling potentially allow for better classification of these tumors and separation of the tumors into different prognostic groups.13-17

MOLECUL A R PATHO GENESIS

Recently, there has been important progress in our understanding of the molecular pathogenesis of malignant gliomas, and especially the importance of cancer stem cells.18,19 Malignant transforma-tion in gliomas results from the sequential accu-mulation of genetic aberrations and the deregu-lation of growth-factor signaling pathways (Fig. 1

and 3).18,22 Glioblastomas can be separated into two main subtypes on the basis of biologic and genetic differences.18,22 Primary glioblastomas typ-ically occur in patients older than 50 years of age and are characterized by EGFR amplification and mutations, loss of heterozygosity of chromosome 10q, deletion of the phosphatase and tensin ho-mologue on chromosome 10 (PTEN), and p16 de-letion. Secondary glioblastomas are manifested in younger patients as low-grade or anaplastic astro-cytomas and transform over a period of several years into glioblastomas. These tumors, which are much less common than primary glioblastomas, are characterized by mutations in the p53 tumor-suppressor gene,23 overexpression of the platelet-derived growth factor receptor (PDGFR), abnor-malities in the p16 and retinoblastoma (Rb) pathways, and loss of heterozygosity of chromo-some 10q.18,24 Secondary glioblastomas have tran-scriptional patterns and aberrations in the DNA copy number that differ markedly from those of primary glioblastomas.18,22 Despite their genetic differences, primary and secondary glioblastomas are morphologically indistinguishable and respond similarly to conventional therapy, but they may re-spond differently to targeted molecular therapies.

High-grade oligodendrogliomas are character-ized by the loss of chromosomes 1p and 19q (in 50 to 90% of patients).1 Progression from low-grade to anaplastic oligodendroglioma is associ-ated with defects in PTEN, Rb, p53, and cell-cycle pathways.1

Deregulated Growth Factor Signaling

The most common defects in growth-factor sig-naling involve EGFR and PDGFR (Fig. 3).18 Am-plification of EGFR occurs almost exclusively in primary glioblastomas and is seen in approximate-ly 40 to 50% of patients with that type of tumor. About half of the tumors with EGFR amplifica-tion express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII, that lacks the extracellular ligand-binding domain (exons 2 through 7).14,18 This characteristic variant has become an important therapeutic target for ki-nase inhibitors, immunotoxins, and peptide vac-cines.3,18 Recently, activating mutations in the ex-tracellular domain of EGFR have been identified.25 PDGF signaling is a key regulator of glial devel-opment,26 and both ligand and receptors are fre-quently expressed in gliomas, creating an auto-crine loop that stimulates proliferation of the




tumor.18 Growth factor–receptor signaling, through intermediate signal-transduction generators, re-sults in the activation of transcriptional programs for survival, proliferation, invasion, and angio-genesis. Common signal-transduction pathways activated by these growth factors are the Ras– mitogen-activated protein (MAP) kinase path-way, which is involved in proliferation and cell-cycle progression, and the phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian 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 neg-atively 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 up-regulation of vascular endothelial growth factor (VEGF) and angiogenesis.28,29 EGFR, PDGFR, and VEGF-receptor (VEGFR) pathways also play an

important role in the normal development of the nervous system by promoting the proliferation of multipotent stem cells. Other developmental path-ways that contribute to the biologic features of gliomas are those involving sonic hedgehog, wing-less, 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 in-vestigation as treatment for gliomas.

Role of Stem Cells in Pathogenesis and Resistance to Therapy

Although the genetic and signaling pathways in-volved in the development of malignant gliomas

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PDGFA/PDGFR-α overexpressed (~60%)

Low-Grade Astrocytoma (5–10 yr)*(WHO Grade II) Low-Grade Oligodendroglioma (5–10 yr)*

(WHO Grade II)

Anaplastic Astrocytoma (2–3 yr)*

(WHO Grade III)LOH 10q (~70%) DCC loss (~50%)PDGFR-α amplified (~10%)

Anaplastic Oligodendroglioma (3–5 yr)*

PTEN mutated (~10%)(WHO Grade III)

PI3K mutated/amplified (~10%) VEGF overexpressed

Secondary Glioblastoma (12–15 mo)*(WHO Grade IV) (WHO Grade IV)

Cell-of-Origin: Differentiated Glial or Stem or Progenitor Cells

Olig2 expression (100%)P53 mutated (>65%)

Olig2 expression (100%) Olig2 expression (100%) EGFR amplified (~40%)EGFR overexpressed (~60%)EGFR mutated (~20–30%)MDM2 amplified (~10%)MDM2 overexpressed (>50%)LOH 10q (~70%) P16Ink4a/P14ARF loss (~30%)PTEN mutated (~40%)PI3K mutated/amplified (~20%)RB mutatedVEGF overexpressed

LOH 1p, 4q, 19qEGFR overexpressedPDGF/PDGFR overexpressed

P16Ink4a/P14ARF loss RB mutated (~65%)p53 mutated PTEN lossLOH 9p, 10qCDK4/EGFR/MYC amplifiedVEGF overexpressed

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

Primary Glioblastoma (12–15 mo)*

Figure 1. Pathways in the Development of Malignant Gliomas.

Genetic and chromosomal alterations involved in the development of the three main types of malignant gliomas (primary and secondary glioblastomas and anaplastic oligodendroglioma) are shown. Oligodendrocyte transcription factor 2 (Olig2) (blue) and vascular endo-thelial growth factor (VEGF) (red) are expressed in all high-grade gliomas. Median lengths of survival (asterisks) are shown. A slash indicates one or the other or both. DCC denotes deleted in colorectal carcinoma, EGFR epidermal growth factor receptor, LOH loss of heterozygosity, MDM2 murine double minute 2, PDGF platelet-derived growth factor, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PTEN phosphatase and tensin homologue, and RB retinoblastoma.


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have been relatively well characterized, the cellu-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 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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Figure 2. Pathological Features of Malignant Gliomas.

Panels A and B show the histologic appearance of a glioblastoma, characterized by nuclear pleomorphism, dense cellu-larity, and pseudopalisading necrosis (asterisk) (Panel A, hematoxylin and eosin) as well as vascular endothelial prolifera-tion (asterisk) and mitotic figures (arrows) (Panel B, hematoxylin and eosin). Panels C and D show the histologic features of an anaplastic oligodendroglioma, including the typical perinuclear halo (“fried egg”) appearance (Panel C, hematoxy-lin and eosin) and diffuse Olig2 staining (Panel D, brown color). The proliferation index can be quantified by immunohis-tochemical analysis with the use of Ki67 staining (Panel E, black color), and heterogeneous EGFR amplification by colori-metric in situ hybridization showing more than two signals (brown spots in nuclei) in almost all tumor cells (Panel F). (Courtesy of Ali G. Saad, M.D., Department of Pathology, Brigham and Women’s Hospital.)




by escaping the mechanisms that control prolif-eration 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 ap-pear to be critical for generating these tumors.36,38 Recent studies suggest that glioma stem cells pro-duce VEGF and promote angiogenesis in the tu-mor microenvironment.39 In addition, tumor stem cells appear to require a vascular niche for opti-mal function.40 These observations raise the pos-sibility 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 malig-nant gliomas to standard treatments (Fig. 4). Radioresistance in stem cells generally results from the preferential activation of DNA-damage-response pathways,41 whereas chemoresistance re-sults partly from the overexpression of O6-meth-ylguanine−DNA methyltransferase (MGMT), the up-regulation of multidrug resistance genes, and the inhibition of apoptosis.42-44 Therapeutic strat-egies that effectively target stem cells and over-come their resistance to treatment will be neces-sary 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, sei-zures, focal neurologic deficits, confusion, mem-ory loss, and personality changes. Although the classic headaches that are suggestive of increased intracranial pressure are most severe in the morn-ing and may wake the patient from sleep, many patients experience headaches that are indistin-guishable from tension headaches. When severe, the headaches may be associated with nausea and vomiting.

Imaging

The diagnosis of malignant gliomas is usually suggested by magnetic resonance imaging (MRI) or computed tomography. These imaging studies

typically show a heterogeneously enhancing mass with surrounding edema. Glioblastomas frequent-ly have central areas of necrosis and more exten-sive peritumoral edema than that associated with anaplastic gliomas.45 Functional MRI may help define the relationship of speech and motor ar-eas to the tumor and aid in the planning of sur-gery. Diffusion-weighted imaging, diffusion ten-sor imaging, dynamic contrast-enhanced MRI to measure vessel permeability, and perfusion im-aging to measure relative cerebral blood volume are increasingly used as diagnostic aids and as a means of monitoring the response to therapy.46

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 platelet-derived growth factor (PDGF) receptor include ima-tinib, dasatinib, and tandutinib; those that target vas-cular endothelial growth factor (VEGF) receptor include cediranib, pazopanib, sorafenib, sunitinib, vata-lanib, vandetanib, and XL184. EGF receptor antibodies include cetuximab and panitumumab. Farnesyl trans-ferase 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 inhib-itors 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 ki-nase, ERK extracellular signal-regulated kinase, FGF fi-broblast growth factor, FTI farnesyl transferase inhibi-tors, 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 phos-phatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, PTEN phosphatase and tensin ho-mologue, RAF v-raf 1 murine leukemia viral oncogene homologue 1, RAS rat sarcoma viral oncogene homo-logue, 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 tu-berous sclerosis gene 1 and 2. Red text denotes inhibi-tors. Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21


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Proton magnetic resonance spectroscopy detects the levels of metabolites and may help differenti-ate 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 turn-over) and a decrease in the N-acetyl aspartate peak (reflecting decreased neuronal cellularity), as com-pared with the findings in unaffected areas of the brain.45,46 Positron-emission tomography that uses




isotopes such as 18F-fluorodeoxyglucose, 18F-flu-oro-l-thymidine, 11C-methionine, and 3,4-dihy-droxy-6-18F-fluoro-l-phenylalanine is being eval-uated for its usefulness in diagnosis and in monitoring the response to therapy.47

In up to 40% of cases, the MRI studies that

are performed in the first month after radiothera-py show increased enhancement.48 In 50% of these cases, the increased enhancement reflects a tran-sient increase in vessel permeability as a result of radiotherapy, a phenomenon termed “pseudopro-gression,” which improves with time.48 Differen-

Figure 4. Resistance Mechanisms in Glioma Cells.

Normal neural stem cells self-renew and give rise to multipotential progenitor cells that form neurons, oligodendro-glia, 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).


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tiating this transient effect from true progres-sion of the cancer can be challenging initially, even with advanced imaging techniques.

TR E ATMEN T

General Medical Management

Much of the care of patients with malignant gliomas involves general medical management. The most common problems include seizures, per-itumoral edema, venous thromboembolism, fa-tigue, and cognitive dysfunction.49 Patients who present with seizures should be treated with an-tiepileptic drugs. Since antiepileptic drugs that induce hepatic cytochrome P-450 enzymes, such as phenytoin and carbamazepine, increase the me-tabolism of many chemotherapeutic agents, anti-epileptic drugs that do not induce these enzymes, such as levetiracetam, are generally preferred. The use of prophylactic antiepileptic drugs in patients with malignant gliomas who have never had a seizure is controversial. The American Academy of Neurology issued a practice guideline indicating that there is no evidence that prophylactic anti-epileptic drugs are beneficial and advises against the routine use of antiepileptic drugs in patients with brain tumors who have not had seizures.50

Corticosteroids such as dexamethasone are fre-quently used to treat peritumoral edema. Cush-ing’s syndrome and corticosteroid myopathy may develop in patients who require prolonged treat-ment with high doses of corticosteroids. Patients with brain tumors who receive corticosteroids are at increased risk for Pneumocystis jiroveci pneumoni-tis, and prophylactic antibiotic therapy should be considered,49 although a recent meta-analysis did not show a benefit from this approach.51 As the rate of survival among patients with malignant glioma improves, long-term complications from treatment with corticosteroids, including osteo-porosis and compression fractures, are becoming increasingly evident, and preventive measures, such as treatment with vitamin D, calcium sup-plements, and bisphosphonates, should be con-sidered. Novel therapies such as corticotropin-releasing factor, bevacizumab (a humanized VEGF monoclonal antibody), and VEGFR inhibitors de-crease peritumoral edema and may reduce the need for corticosteroids.49,52

Patients with malignant gliomas are at in-creased risk for venous thromboembolism from leg and pelvic veins, with a cumulative incidence

of 20 to 30%.49,53 The risk of intratumoral hem-orrhage associated with anticoagulation therapy in patients with gliomas who have venous throm-boembolism is low,49,54 whereas inferior vena cava filters are associated with high complication rates.55 Unless a patient with malignant glioma and venous thromboembolism has an intracere-bral hemorrhage or other contraindications, it is generally safe to provide anticoagulation therapy for the venous thromboembolism. Low-molecular-weight heparin may be more effective and safer than warfarin.56

Patients with malignant gliomas frequently ex-perience fatigue and may benefit from treatment with modafinil or methylphenidate.57 Methyl-phenidate may also help abulia, and donepezil58 and memantine may reduce memory loss, although evidence supporting these approaches remains limited. Depression is underdiagnosed in patients with malignant gliomas, and antidepressants and psychiatric support are often invaluable.59

Specific Therapy for Newly Diagnosed Malignant Gliomas

The standard therapy for newly diagnosed malig-nant gliomas involves surgical resection when fea-sible, radiotherapy, and chemotherapy (Table 1). Malignant gliomas cannot be completely eliminat-ed surgically because of their infiltrative nature, but patients should undergo maximal surgical resection whenever possible. Surgical debulking reduces the symptoms from mass effect and pro-vides tissue for histologic diagnosis and molecu-lar studies. Advances such as MRI-guided neuro-navigation, intraoperative MRI, functional MRI, intraoperative mapping,60 and fluorescence-guid-ed surgery61 have improved the safety of surgery and increased the extent of resection that can be achieved. The value of surgery in prolonging sur-vival is controversial, but patients who undergo extensive resection probably have a modest sur-vival advantage.60-62 Stereotactic biopsies should be performed only in patients who have inoper-able tumors that are located in critical areas.

Radiotherapy is the mainstay of treatment for malignant gliomas. The addition of radiotherapy to surgery increases survival among patients with glioblastomas from a range of 3 to 4 months to a range of 7 to 12 months.63,64 Conventional ra-diotherapy consists of 60 Gy of partial-field exter-nal-beam irradiation delivered 5 days per week in fractions of 1.8 to 2.0 Gy. After standard radio-




therapy, 90% of the tumors recur at the original site.65 Strategies to increase the radiation dose to the tumor with the use of brachytherapy 66 and stereotactic radiosurgery 67,68 have failed to im-prove survival. Newer chemotherapeutic agents,69 targeted molecular agents,20 and antiangiogenic agents70 may enhance the effectiveness of radio-therapy.

Patients who are older than 70 years of age have a worse prognosis than younger patients and rep-resent a particular challenge. Among these pa-tients, radiotherapy produces a modest benefit in median survival (29.1 weeks) as compared with supportive care (16.9 weeks).71 Since older pa-tients often tolerate radiotherapy less well than younger patients, an abbreviated course of radio-therapy (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 blood–brain barrier) alone73 may be con-sidered, since the outcomes with these approach-es are similar to the outcomes with conventional radiotherapy regimens.

Chemotherapy is assuming an increasingly im-portant 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 meta-analyses have suggested that adjuvant chemother-

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 con-tributes to resistance to temozolomide. In a com-panion study to the EORTC–NCIC study reported by Stupp et al., tumor specimens from the pa-

Table 1. Summary of Current Treatments for Malignant Gliomas.*

Type of Tumor Therapy

Newly diagnosed tumors

Glioblastomas (WHO grade IV) Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant TMZ or carmustine wafers (Gliadel)†

Anaplastic astrocytomas (WHO grade III)

Maximal surgical resection, with the following options after surgery (no ac-cepted standard treatment): radiotherapy, plus concomitant and adjuvant TMZ or adjuvant TMZ alone†

Anaplastic oligodendrogliomas and anaplastic oligoastrocy-tomas (WHO grade III)

Maximal surgical resection, with the following options after surgery (no ac-cepted standard treatment): radiotherapy alone, TMZ or PCV with or with-out radiotherapy afterward, radiotherapy plus concomitant and adjuvant TMZ, or radiotherapy plus adjuvant TMZ†‡

Recurrent tumors Reoperation in selected patients, carmustine wafers (Gliadel), conventional chemotherapy (e.g., lomustine, carmustine, PCV, carboplatin, irinotecan, etoposide), bevacizumab plus irinotecan, experimental therapies‡

* Data are from Sathornsumetee et al.,3 Furnari et al.,18 Chi and Wen,20 and Sathornsumetee et al.21 PCV denotes procar-bazine, 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 ad-ministered 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.


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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 ac-tivity and increasing the susceptibility of the tu-mor cells to temozolomide. Patients with glioblas-toma 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 regard-less of MGMT promoter methylation status. How-ever, if the importance of MGMT promoter methy-lation 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-benzylgua-nine, and inhibitors of other repair enzymes, such as poly-(ADP-ribose)-polymerase, are in progress.

Another chemotherapeutic approach involves the implantation of biodegradable polymers con-taining 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 inves-tigated the use of these polymers in patients with newly diagnosed malignant gliomas, median sur-vival increased from 11.6 months to 13.9 months (P = 0.03).77 This survival advantage was main-tained at 2 and 3 years.78

Therapy for Anaplastic Gliomas

Anaplastic astrocytomas are treated with radio-therapy and either concurrent and adjuvant temo-zolomide (as for glioblastomas) or adjuvant temo-zolomide alone. Currently, there are no findings from controlled trials that support the use of con-current temozolomide in patients with anaplastic astrocytomas.

Anaplastic oligodendrogliomas and anaplas-tic oligoastrocytomas are an important subgroup of malignant gliomas that are generally more re-sponsive to therapy than are pure astrocytic tu-mors.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. Tu-mors in patients with the 1p and 19q codeletion are particularly sensitive to chemotherapy with PCV — procarbazine, lomustine (CCNU), and vin-cristine — 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 chemo-sensitivity 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 involv-ing patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, reflecting a par-adigm shift in the design of clinical trials for pa-tients with these tumors.

Two large phase III studies of PCV chemother-apy with radiotherapy, as compared with radio-therapy alone, in patients with newly diagnosed anaplastic oligodendrogliomas or anaplastic oli-goastrocytomas, have been reported.84,85 In both studies, the addition of chemotherapy to radio-therapy 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 fail-ure of chemotherapy to increase survival may be partly explained by the fact that patients who ini-tially received radiotherapy alone subsequently re-ceived chemotherapy when they had a relapse, so that most patients in both groups eventually re-ceived chemotherapy. In both studies, patients with the codeletion of 1p and 19q had improved survival as compared with those without the code-letion of 1p and 19q. Although most studies involving patients with anaplastic oligodendro-gliomas or anaplastic oligoastrocytomas were con-ducted with PCV chemotherapy, temozolomide is likely to have similar activity and less toxicity79; however, studies directly comparing the two regi-mens 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, re-




operation may be indicated (Table 1). However, sur-gery 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 ste-reotactic reirradiation88 and stereotactic radiosur-gery68 may be beneficial, selection bias may have influenced these results.

The value of conventional chemotherapy for re-current malignant gliomas is modest. In general, chemotherapy is more effective for anaplastic gliomas than for glioblastomas.79,87 Temozolo-mide 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 com-paring favorably with the 31% rate of progression-free survival at 6 months for therapies that were reported to be ineffective.90 In contrast, temozolo-mide 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, carbo-platin, procarbazine, irinotecan, and etoposide. Carmustine wafers have modest activity, increas-ing the median survival by approximately 8 weeks in patients with recurrent glioblastomas.92

IN V ES TIG ATIONA L THER A PIES

Targeted Molecular Therapies

The improved understanding of the molecular pathogenesis of malignant gliomas has allowed a more rational use of targeted molecular thera-pies (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 (Ta-ble 2). Single agents have only modest activity, with response rates of 0 to 15% and no prolonga-tion of 6-month progression-free survival.3,20,21 These disappointing results are due to several fac-tors. 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

have poor penetration across the blood−tumor bar-rier. There has been considerable interest in iden-tifying molecular features of the tumor that pre-dict a response, so that patients who are most likely to benefit can be selected for a particular treatment. EGFR inhibitors appear to be more ef-fective 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 PI3K–Akt pathway, as indicated by an increase in phosphorylated Akt, generally do not have a re-sponse.100 Current experimental strategies to in-crease the effectiveness of targeted molecular ther-apies 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

Malignant gliomas are among the most vascular of human tumors,18 making them especially at-tractive targets for angiogenesis inhibitors.29 Al-though older antiangiogenic agents such as tha-lidomide had only modest activity,101 newer and more potent angiogenesis inhibitors show prom-ising activity. In preliminary studies, treatment with the combination of bevacizumab and irino-tecan was associated with a low incidence of hem-orrhage 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 inhibi-tion 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 pa-tients who were receiving treatment with temozo-lomide.91 Recently, a large, randomized phase II trial of bevacizumab alone and bevacizumab with irinotecan was completed. Preliminary results con-firmed the safety of bevacizumab and showed an increase in the 6-month rate of progression-free survival to 35.1% for patients receiving bevacizu-


Medical Progress


Table 2. Selected Investigational Treatments for Malignant Gliomas.*

Type of Treatment Example

Convection-enhanced surgical delivery of pharmacologic agent

Cintredekin besudotox

Drugs to overcome resistance to TMZ

Dose-dense TMZ

MGMT inhibitors O6-benzylguanine

PARP inhibitors BSI-201, ABT-888

New chemotherapies RTA744, ANG1005

Antiangiogenic therapies

Anti-αvβ5 integrins Cilengitide

Anti-hepatocyte growth factor AMG-102

Anti-VEGF Bevacizumab, aflibercept (VEGF-Trap)

Anti-VEGFR Cediranib, pazopanib sorafenib, sunitinib, vandetinib, vatalanib, XL184, CT-322

Other agents Thalidomide

Targeted molecular therapies

Akt Perifosine

EGFR inhibitors Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab, cetuximab

FTI inhibitors Tipifarnib, lonafarnib

HDAC inhibitors Vorinostat, depsipeptide, LBH589

HSP90 inhibitors ATI3387

Met XL184

mTOR inhibitors Everolimus, sirolimus, temsirolimus, deforolimus

PI3K inhibitors BEZ235, XL765

PKCβ Enzastaurin

PDGFR inhibitors Dasatinib, imatinib, tandutinib

Proteasome Bortezomib

Raf Sorafenib

Src Dasatinib

TGF-β AP12009

Combination therapies Erlotinib plus temsirolimus, gefitinib plus everolimus, gefitinib plus sirolimus, sorafenib plus temsirolimus, erlotinib, or tipifarnib, pazopanib plus lapatinib

Immunotherapies

Dendritic cell and EGFRvIII peptide vaccines DCVax, CDX-110

Monoclonal antibodies 131I-anti-tenascin antibody

Gene therapy

Other therapies 131I-TM-601

* 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-methylguanine−DNA methyltransferase, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose) polymerase, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase, PKCβ protein kinase C β, TGF transforming growth factor, TMZ temozolomide, and VEGFR vascular endothelial growth factor receptor.




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 pro-longation 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 in-terest 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.

Other Therapies

Other investigational therapies for malignant gliomas include chemotherapeutic agents that

cross the blood−tumor 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 (Ta-ble 2).109

PRO GNOS TIC FAC T OR S

The most important adverse prognostic factors in patients with malignant gliomas are advanced age, histologic features of glioblastoma, poor Kar-nofsky performance status, and unresectable tu-mor.110 There are ongoing efforts to identify bio-logic and genetic alterations in the tumors that may provide additional prognostic information, as well as guidance in making decisions about opti-mal therapy.15,16,82

33p9

A B

DC

E F

HG

AUTHOR

FIGURE

JOB: ISSUE:

4-CH/T

RETAKE 1st

2nd

SIZE

ICM

CASE

EMail LineH/TCombo

Revised



REG F

FILL

TITLE3rd

Enon ARTIST:

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7-31-08

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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 combi-nation of erlotinib (an inhibitor of epidermal growth factor receptor [EGFR]) and sirolimus (an inhibitor of the mam-malian target of rapamycin [mTOR]). T1-weighted images obtained after the administration of gadolinium show a re-duction in the size of the enhancing tumor from the pretreatment image (Panel A) to the image obtained 2 months after treatment (Panel B), with fluid-attenuated inversion recovery (FLAIR) studies showing a reduction of edema from the pretreatment image (Panel C) to the post-treatment image (Panel D). Panels E through H show MRI scans of a recurrent glioblastoma in a patient who was treated with a combination of bevacizumab and irinotecan. T1-weighted images obtained after the administration of gadolinium show a reduction in the size of the enhancing tu-mor from the image obtained before treatment (Panel E) to the image obtained 7 months after treatment (Panel F) and an associated reduction of edema from the pretreatment FLAIR image (Panel G) to the post-treatment FLAIR image (Panel H).


Medical Progress


SUMM 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 treat-ment. As our understanding of the molecular cor-relates of response improves, it may be possible to select the most appropriate therapies on the basis of the patient’s tumor genotype. These ad-vances provide real opportunities for the develop-ment of effective therapies for malignant gliomas.

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 Schering-Plough, 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 Bristol–Myers 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 help-ful comments.

This article is dedicated to the memories of Elizabeth Atkins, Will Kraft, and John Kenney.

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New England Journal of Medicine

CORRECTION

Malignant Gliomas in Adults

Malignant Gliomas in Adults . The institution in Dr. Wen’s address

(page 492) should have read `̀ Dana–Farber/Brigham and Women’s

Cancer Center.´́ In Table 2 (page 503), the `̀ Dendritic cell and

EGFRvIII peptide vaccines´́ row should have included the following

entry: DCVax, CDX-110. The article has been corrected on the Jour-

nal ’s Web site at www.nejm.org.

N Engl J Med 2008;359:877-a


malignant gliomas in adult

Documents

chromosome malignant

case of anaplastic gliomas

majority of malignant

development of gliomas

increased risk of gliomas

reduced risk of gliomas

alignant gliomas account

family history of gliomas