Review

10.1517/13543780903052764 © 2009 Informa UK Ltd ISSN 1354-3784 1061All rights reserved: reproduction in whole or in part not permitted

Glioblastomamultiforme:areviewofwherewehavebeenandwherewearegoingCory Adamson†, Okezie O Kanu, Ankit I Mehta, Chunhui Di, Ningjing Lin, Austin K Mattox & Darell D Bigner†Duke Medical Center, Durham, North Carolina, USA

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate ‘where we have been’ with this fatal disease and ‘where we are going’ with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.

Keywords: GBM, genetics, glioblastoma multiforme, oncogenomics, signaling cascades

Expert Opin. Investig. Drugs (2009) 18(8):1061-1083

1. Overviewofglioblastoma

Glioblastoma (GBM) is the most common primary CNS tumor in the USA and European countries, with about 3 in 100,000 people newly diagnosed with GBM each year, accounting for > 51% of all gliomas (Figure 1) [1]. Gliomas are categorized as World Health Organization (WHO) grades I – IV, based on histological char-acteristics, which carries prognostic and survival correlates. Glioblastoma is a WHO grade IV glioma, the most malignant grade. For decades, it has been known that some gliomas of lower WHO grade can recur, progress, or transform into GBM. These have been termed secondary GBMs, whereas de novo GBM tumors are termed primary GBMs. The genetic heterogeneity of GBMs underscores the existence of these two subtypes. For example, recent genome-wide studies have identified mutations in NADP+-dependent isocitrate dehydrogenase genes that appear frequently in secondary GBM [2,3].

The mean age of primary GBM patients is about 62, whereas the mean age of secondary GBM is about 45 [4,5]. The age distribution of GBM varies more with

1. Overview of glioblastoma

2. Glioblastoma pathology

and molecular biology

3. Glioblastoma immunology

4. ‘Where we have been’

5. ‘Where we are now’

6. ‘Where we are going’

7. Conclusion

8. Expert opinion

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the secondary type. Primary GBM develops more frequently in males than in females (M:F ratio = 3:1), whereas the reverse is the case for secondary GBM [4,6-11]. Primary GBM is rarely seen in younger patients, constituting only 8.8% of all childhood CNS tumors [12].

Population-based studies report that the overall survival of patients with newly diagnosed GBM is 17 – 30% at 1 year, and only 3 – 5% at 2 years, despite access to state-of-the-art modalities of therapy [4,13,14]. Recent meta-analyses of clinical trials show that 2-year survival rates can reach 13 – 26%, emphasizing that patients fare better in clinical trials, probably due to improved healthcare, access to therapies, and selection bias [15]. Survival rates do not differ between men and women, but they are clearly higher for younger patients. Five-year survival rates are about 13% for patients aged 15 – 45 years, and only 1% for those aged ≥ 75 years [13].

The etiology of GBM is unknown. While the incidence of gliomas has been reported by some to be on the rise [16,17], the predisposing factors are poorly understood [18-21]. The only proven environmental risk factor for gliomas is expo-sure to ionizing radiation, such as children irradiated for leukemia [22]. Many other factors have been suggested, such as exposure to chemical carcinogens in occupations such as rubber manufacturing, petroleum production, vinyl chlo-ride, pesticides, forestry work, and cleaning services, as well as passive smoking exposure, although none of these are established causes [19]. Interestingly, increasing socioeco-nomic status increases risk for gliomas [23]. A slight increase risk of ipsilateral gliomas was seen in one meta-analysis studying cellphone use for >10 years; however, this risk is

probably nonexistent today, since cellphone technology has significantly changed over the past decade [24]. Caucasians are more frequently affected than their Asian or African counterparts [5,25-27]. About 5% of gliomas represent familial aggregations, with some seen in known syndromes such as Cowden’s disease, Li–Fraumeni syndrome, and neurofibro-matosis [18]. Isolated studies have noted some molecular cor-relations with longer survival, such as O6-methylguanine-DNA methyltransferase (MGMT) hypermethylation; however, no molecular event has become routinely accepted as a prog-nostic factor, although patients with IDH1 and IDH2 mutations have a much better prognosis [28]. Many analyses have shown that no significant difference exists among clini-cal and molecular factors, except for IDH1 and IDH1 mutations, for longer survival of patients with primary or secondary GBM, except possibly younger age and a good initial Karnofsky Performance Status (KPS) [4,5,28]. Age and KPS provide the primary prognostic factors in the com-monly used recursive partitioning analyses seen in the Radi-ation Therapy Oncology Group and European Organization for Research and Treatment of Cancer prognostic classes (Table 1) [29,30].

The most common presenting symptoms and signs for patients with GBM are progressive focal neurologic deficits, headaches, and seizures. Even though the reported incidence of many asymptomatic benign CNS tumors is increasing due to the increasing prevalence of neuroimaging, the aggres-sive growth of GBMs usually precludes incidental discovery of these. Diagnosis typically begins with suspicious findings on MRI, including T1-weighted images with and without

All other gliomas, 11.1%

Ependymomas, 5.8%

Oligodendrogliomas, 8.4%

Pilocytic astrocytoma (WHO I), 5.8%

Diffuse astrocytoma(WHO II), 1.5%

Anaplastic astrocytoma(WHO III), 7.5%

GBM (WHO IV), 51.2%

All other astrocytomas,8.7%

Figure1.DistributionofallprimaryCNSgliomas(n=26,630). Astrocytomas account for 75% of all gliomas. Astrocytomas arise specifically from astrocytes, whereas gliomas refer to primary CNS tumors that arise from astrocytes, oligodendrogliomas, or ependymal cells.Figure adapted from more recent Central Brain Tumor Registry of the United States [1].

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gadolinium and T2-weighted images. If patients are unable to undergo MRI, a contrast-enhanced CT scan may be useful; however, this modality remains far inferior in image detail. Glioblastoma is classically hypointense to isointense, with a ring-pattern of enhancement on gadolinium-enhanced T1 images, and is hyperintense on both T2 and FLAIR images. It can be focal, multifocal, or diffuse (gliom-atosis cerebri). The majority of GBM tumors are found in the frontal lobes of the supratentorial compartments, but they also occur in all cortical areas, the cerebellum, brain-stem, and spinal cord. The vast majority of neoplastic cells are found within the tumor bed and within 2 cm of the enhancing borders; however, migrating cells can be found several centimeters away from the tumor and even in the contralateral hemisphere. Magnetic resonance spectroscopy (MRS), MR perfusion, and F18-fluorodeoxyglucose-positron emission tomography (FDG-PET) are more sophisticated imaging tools that can help delineate varied metabolic rates and therapeutic responses. They can be par-ticularly useful for differentiating tumor recurrence from benign radiation necrosis.

Table1.Prognosticclassesmostcommonlyused,asproposedbyRTOGandEORTC.

Class Prognosticfactor Mediansurvival(months)

RTOG

III Age < 50, KPS 90 – 100 17.9

IV Age < 50, KPS < 90

Age > 50, resection, no neurologic deficits

11.1

V Age > 50, KPS 70 – 100, resection with neurologic deficits or only biopsy with > 54.4 Gy

Age > 50, KPS < 70, no neurologic deficits

8.9

VI Age > 50, KPS 70 – 100, biopsy only with < 54.4 Gy

Age > 50, KPS < 70, neurologic deficits

4.6

EORTC

III Age < 50, WHO PS 0 17

IV Age < 50, WHO PS 1 – 2

Age ≥ 50, GTR, MMSE ≥ 27 15

V Age ≥ 50, biopsy only, MMSE < 27 10

Note: Age and KPS are the most uniformly used prognostic factors, followed by

extent of surgical resection and completion of adjuvant therapies.

EORTC: European Organization for Research and Treatment of Cancer; GTR: Gross

total resection; KPS: Karnofsky performance status; MMSE: Mini-mental status

examination; PS: Performance Status; RTOG: Radiation Therapy Oncology

Group; WHO: World Health Organization.

2. Glioblastomapathologyandmolecularbiology

Based on a histopathologic diagnosis, GBM consists of poorly differentiated neoplastic astrocytes, cellular and nuclear atypia, brisk mitotic activity, diminished apoptosis, neoangiogenesis, vascular thrombosis, and pseudopallisading necrosis [31-33]. Vascular hyperproliferation and necrosis are essential diagnostic features that set GBM apart from lower-grade gliomas. Despite its highly invasive and proangiogenic properties, GBM, like most other malignant CNS tumors, does not metastasize outside the CNS.

Despite a common clinical presentation and histology, GBM has clearly been demonstrated to be a genetically heterogeneous tumor. Current understanding of the molecular characteristics of this disease has demonstrated that there are unlikely to be single genetic or cellular events that can be effectively targeted for all patients. Instead, future therapies may require some individualization for each patient’s tumor genotype or proteomic profile. The birth of this century witnessed a new era of investigational drugs, transitioning from the traditional nonspecific chemotherapies of the past to target-specific, often molecular-based, drugs developed in response to our new understanding of the molecular biology of this deadly tumor.

Recent comprehensive genetic screens of GBM have confirmed that genetic alterations are scattered across the entire genome, affecting numerous chromosomes [3,34]. Par-ticularly common regions of loss include areas on 1p, 6q, 9p, 10p, 10q, 13q, 14q, 15q, 17p, 18q, 19q, 22q, and Y [35-40]. Many of these genetic losses represent loss of specific tumor suppressor genes with direct effects on gliomagenesis; how-ever, some of these losses probably represent the inherent genomic instability that develops in tumor cells. Loss of heterozygosity (LOH) on chromosome 10 is the most fre-quent genetic alteration in GBM, occurring in 60 – 80% of cases [41]. Gains of gene expression due to genetic alterations at the genomic level have been demonstrated in GBM in the form of duplication of entire chromosomes, intrachro-mosomal amplification of specific alleles, extrachromosomal amplification (often in the form of double minutes [dmins]), and activating mutations [40,42,43]. These forms of increased gene expression (oncogenic) occur much less frequently than losses of gene expression. Clearly, the most common oncogenic event is amplification of the EGFR gene on chromosome 7, often in the form of dmins [25,44].

Gliomagenesis also involves errors in DNA replication, DNA repair, chromosomal segregation, and alteration of numerous signaling cascades not directly attributed to genomic mutations. This collection of genetic and cellular alterations gives rise to the ‘mutator phenotype’ in glioma cells [45]. Central to this mutator phenotype are DNA repair mechanisms. There are at least four DNA repair pathways that may go awry in GBMs, including nucleotide excision repair, base excision repair, mismatch repair, and direct

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reversal of lesions in recombination [45,46]. As one well-studied example, elevated levels of the DNA repair enzyme MGMT have been demonstrated in GBM [47]. MGMT specifically removes promutagenic alkyl groups from the O6-position of guanine in DNA. Therefore, MGMT protects cells against carcinogenesis induced by alkylating agents. Repair of O6-alkylguanine adducts by tumor cells has been implicated in drug resistance, since it reduces the cytotoxicity of alkylating chemotherapeutic agents [48]. Loss of MGMT expression may be caused by methylation of promoter CpG islands, which has been observed in gliomas [49,50].

Despite the development of a mutator phenotype and the plethora of cellular genetic alterations it probably entails, there are a number of discrete genetic events and signaling pathways that appear to be central to the initiation and pro-gression of GBM (Figure 2) [34]. In GBM, aberrant EGFR and other tyrosine kinase receptor autocrine signaling pathways may be the most often-cited pathways. These lead to robust alterations in cellular development, proliferation, migration, and vacularization. EGFR overexpression is also more common in primary (40 – 60%) than in secondary (< 10%) GBMs [9]. Amplification of the EGFR gene is often associated with structural alterations in the gene. Seven major mutated vari-ants of EGFR have been identified, the most common being variant III (EGFRvIII), which is present in 20 – 50% of GBMs with EGFR amplification [51-54]. In addition to enhancing growth, proliferation, migration, and tumor neovascularization, this truncated receptor also confers resistance to chemo-therapies such as cisplatin through modulation of Bcl-XL and caspases in cell death pathways [55]. Platelet-derived growth factor receptor (PDGFR) is a similar receptor expressed in most types of gliomas [56], whereas EGFR is expressed mainly in GBM [57]. PDGFR signals through PI3K and PLC-γ [58].

In GBM, specific mutations affecting Ras are very rare; however, high levels of Ras guanosine triphosphate (GTP) have been documented in cell lines and primary tumors, suggesting that this signaling pathway is activated by upstream factors such as receptor tyrosine kinase activation [59]. Another major way of activating this pathway is via the loss of neurofibromin function, the protein product of the large neurofibromatosis 1 (NF1) gene. Ras-GTP is downstream of growth factor receptors at a major signal transduction crossroad, translating extrinsic messages into the Raf-MAPKK-ERK, or into either the PI3K-PKB or the PI3K-Rac-Rho pathways. These influence cell survival and migration.

The majority of malignant brain tumors, including GBM, demonstrate inactivating mutations in the TP53 pathway, the retinoblastoma (RB1) pathway, or both [60-63]. These two pathways affect numerous cellular functions and inter-act with each other. The TP53 transcription factor is short-lived and is upregulated in response to cellular stress such as radiation exposure, DNA strand breaks, and toxins. It facilitates DNA repair by halting the cell cycle for repair enzymes to work; or if the damage is too great, it induces

cell death. Mutations of TP53 occur in some familiar tumor syndromes with established associations with malignant gliomas (e.g., in Li–Fraumeni syndrome), which underscores its relevance in the pathogenesis of malignant gliomas [64]. RB1 controls the transition from G1 into S-phase of the cell cycle by inhibiting the action of elongation factor E2F1, and its expression is commonly altered in GBM. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phos-phorylates the RB1 protein, thereby increasing release of the E2F1 transcription factor that activates genes involved in the G1-to-S transition [65].

Mutations of phosphatase tensin homolog (PTEN) on chromosome 10q23, also called MMAC1 and TEP1, occur frequently in familial cancer syndromes, such as Cowden’s syndrome and Bannayan–Riley–Ruvalcaba syndrome, which include GBM as part of the clinical spectrum [66,67]. PTEN contains a central catalytic phosphatase core domain that negatively regulates phosphatidylinositol-3 kinase (PI3K) by dephosphorylating phosphatidylinositol-3,4,5 triphosphate (PIP3) and phosphatidylinositol-3,4 diphosphate (PIP2) [68]. In the case of mutant PTEN, the elevated lipid second messenger PIP3 is used by PI3K to hyperphosphorylate protein kinase B (PKB)/Akt [69]. This modulates the activity of proteins that play a critical role in cell survival, invasion, and proliferation [70].

3. Glioblastomaimmunology

The relatively recent realization that a robust immune reaction can be elicited in the CNS has provided another excited source of investigational drugs for treating GBM (see ‘Immunotherapies’, Table 3). Glioblastoma also alters the immunologic profile of the normal CNS environment, pro-viding additional opportunities for exploring immune-based therapies [69]. Glioma cells express numerous tumor-associated antigens [71,72] that mostly exhibit immunosuppressive activ-ities, such as hindering cell-mediated immunity. Other signs of an altered immune system seen in GBM include cutane-ous anergy, lymphopenia, impaired antibody production, reduced lymphocyte protein synthesis, and diminished lym-phocyte responsiveness [73-84]. Many complex interactions between glioma cells and immune cells are thought to be mediated by glioma-derived cytokines such as IL-6, IL-8, TGF-β2, and VEGF. Additionally, glioma cells are thought to induce expression of immunosuppressive factors from other cells within the environment, such as IL-10 and pros-taglandins from monocytes [85]. Some of these factors over-expressed in GBM have multiple effects. VEGF, which plays a key role in tumor neoangiogenesis, also inhibits the matu-ration of dendritic cells from progenitor cells originating from the bone marrow and promotes GBM tumor cell pro-liferation. Exploiting the immune system for investigational agents may go a long way to enhancing the patient’s own immunotherapy against malignant gliomas and directly killing glioma cells. Indeed, several clinical trials are now in progress testing immune modulating and therapies (see section 6).

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4. ‘Wherewehavebeen’

Clinical research in GBM has a long and prolific history, with reports of hundreds of various types of clinical trials being published. Indeed, the number of clinical reports of treatment modalities that has been tested makes summarization and interpretation almost impossible. However, one can make significant observations by examining the history of the gold standard clinical trial design in GBM, namely Phase III randomized, controlled trials (RCTs) (Table 2). Numerous early RCTs, even back to the 1960s, were well designed with appropriate randomization schemes and control arms, providing sound, evidence-based guidelines. Although its mechanism was not clearly understood, radiation therapy (RT) was the first postsurgical adjuvant therapy that consis-tently demonstrated efficacy over the 1960s and early 1970s, typically doubling survival from 4 – 6 to 10 – 11 months. Whole-brain RT quickly became the standard of care and characterized the control arm for future studies. As with other cancers, the nonspecific targeting of rapidly dividing cells by RT proved efficacious for GBM. However, some neural structures (e.g., the optic apparatus) are quite sensitive to RT, limiting the total amount of RT that can be tolerated. RT is restricted to individuals aged > 3 years due to the sensitivity of the newborn brain to RT. Because of the clear benefit of RT, there have been several studies investigating the addition of radiosensitizers (e.g., misonidazole and metronidazole); however, none have consistently shown benefit. Numerous alterations in the RT regimen have been studied, but none have consistently demonstrated improvements in survival, including dose escalations > 60 Gy, hyperfractionation or accelerated superfractionated RT, brachytherapy, neutron versus photon boosts, radioactive targeting agents, or stereotactic radiosurgery with a linear accelerator or gamma-knife. Less RT (50 Gy, 1.8-Gy fractions) has demonstrated a survival advantage in patients aged > 70 years [86]. Radioenhancers such as RSR13, a synthetic modifier of hemoglobin, and motexafin gadolinium are under investigation. The only major change in the delivery of RT that has made it to current standard-of-care treatment regimens is that coned-down or focused RT is as effective as whole-brain RT, eliminating the long-term sequelae associated with whole-brain treatment.

Nitrosourea studies have dominated the history of RCTs in GBM. Meta-analysis suggests some nitrosoureas (BCNU) add a marginal benefit to survival (about 2 months) [15]. Despite modest benefit, systemically administered BCNU universally remained the standard of care for adjuvant chemotherapy until the mid 1990s, when studies in newly diagnosed and recurrent GBM demonstrated a similar benefit (increasing survival by ∼ 2 months) with BCNU (Gliadel®, Esai, Inc., Woodcliff Lake, USA) administered locally to the resection cavity at the time of surgery [87,88]. Gliadel consists of dime-size wafers impregnated with carmustine. Contraindications for its use include direct contact with eloquent cortex (e.g., primary motor cortex) or critical neurovascular structures such as cranial nerves, an

open ventricular system, or an inability to obtain CSF-tight dural surgical closure. Despite the benefit proven in RCTs, this therapy never gained universal acceptance, probably due to unfamiliarity with indications for its use, concern for local side effects, and cost. It still remains an important option. Despite the numerous studies with BCNU spanning over four decades, a single study by Stupp and colleageues in 2005 [99] established a new systemic chemotherapy as the standard of care. Temozolomide, given concomitantly with postoperative RT and followed by continued use for 6 – 12 months after RT, is an orally available therapy with effi-cacy similar to that of BCNU and less toxicity.

One area of extensive investigation is with long-term survivors who survive more than 2 – 3 years with GBM. Some argue that a major contributor to the extended sur-vival for this very small group of patients may be that those patients are involved in clinical trials at academic medical centers: overall outcomes for these patients are improved simply by their involvement in clinical trials. Therefore, all physicians treating GBM patients should be aware of oppor-tunities for referring their patients to these centers. Even if therapies are not proven to be efficacious in clinical trials, patients clearly benefit from the increased surveillance of tumor recurrence, the vigilant search for therapy toxicities, and easier access to services such as counseling and education. The other obvious benefits of RCTs are access to potentially improved therapeutic options and contact with oncology scientists at the forefront of GBM treatment investigation. Major academic centers with active brain tumor programs typically have numerous clinical trial options and will have physicians with the specific training that is needed to care for patients with this complex disease.

5. ‘Wherewearenow’

Surgery has become the cornerstone in the initial treatment of GBM, although it has not yet been validated by pro-spective Phase III RCTs. Retrospective and similar-level studies show that, in general, resection > 98% doubles survival over that following biopsy alone, up to a maximum of about 11 – 12 months [89-92]. GBM infiltrates adjacent brain parenchyma, so complete resection is not possible; however, many neuro-oncology surgeons believe that modern neu-roimaging allows > 98% tumor resection in cases where tumor does not significantly involve eloquent structures (e.g., primary motor cortex). Only maximal cytoreduction of > 98% significantly alters survival, and probably improves a patient’s response to radiotherapy and chemotherapy [92,93]. Submaximal cytoreduction may alleviate immediate mass effect, causing neurological deficits or raised intracranial pressure; however, many neuro-oncology surgeons argue against these treatment attempts because of the anticipated worse outcomes. Residual tumor can behave in a very aggressive and malignant fashion, with enormous edema, and cause worse mass effect acutely when the tumor is reduced only

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6)

N38

– 5

356

– 8

060

00 r

ad o

f w

hole

-bra

in R

T w

ith s

urge

ry in

crea

sed

6 m

sur

viva

l ra

te t

wo

to t

hree

tim

es t

hat

obse

rved

in c

ontr

ol

Wal

ker,

196

7 [1

17]

RT (4

4),

RT+

mith

ram

ycin

(52)

YN

D89

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith m

ithra

myc

in

Wal

ker,

196

9 [9

6]C

onse

rvat

ive

care

(42)

,BC

NU

(68)

,RT

(93)

,RT

+BC

NU

(100

)

Y57

90RT

+BC

NU

incr

ease

d M

ST t

o 8m

fro

m 3

m in

con

trol

s

Reag

an, 1

970

[118

]RT

(22)

,C

CN

U (2

2)RT

+C

CN

U (1

9)

YN

DN

DN

o si

gnifi

cant

diff

eren

ce in

MST

with

CC

NU

Wie

r, 1

971

[119

]RT

(15)

,C

CN

U (1

3),

RT+

CC

NU

(13)

NN

DN

DN

o si

gnifi

cant

diff

eren

ce in

MST

with

CC

NU

Sole

ro, 1

972

[120

]RT

50

Gy

(32)

,RT

+BC

NU

(34)

,RT

+C

CN

U (3

6),

N50

31 –

34

BCN

U o

r C

CN

U in

crea

sed

MST

fro

m 1

0m –

12m

and

16m

, re

spec

tivel

y, w

hen

adde

d to

RT

Wal

ker,

197

2 [1

21]

RT (9

4),

MeC

CN

U (8

1),

RT+

BCN

U (9

2),

RT+

MeC

CN

U (9

1)

Y55

89RT

impr

oved

MST

fro

m 7

.1m

– 8

.5m

com

pare

d to

CC

NU

alo

ne;

RT+

nitr

osou

rea

incr

ease

d M

ST t

o 10

– 1

1m

Not

e: R

CTs

are

list

ed c

hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

ion,

bre

akdo

wn

of c

ontr

ol v

ersu

s tr

eatm

ent

arm

s, y

ear

stud

y be

gan,

pop

ulat

ion

size

, tre

atm

ents

, mul

ticen

ter

stat

us, a

vera

ge a

ge o

f

part

icip

ants

, per

cent

age

of G

BM p

artic

ipan

ts, t

reat

men

ts, a

nd r

esul

ts.

*Tak

en f

rom

sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

Con

trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

DTI

C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

%G

BM: R

ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

grou

p; G

y: G

ray;

HD

-MP:

Hig

h-do

se m

ethy

lpre

dnis

olon

e; H

RT: H

yper

frac

tiona

ted

RT; H

SVTK

/G: H

erpe

s si

mpl

ex v

irus

type

1 t

hym

idin

e ki

nase

and

gan

cicl

ovir

gene

the

rapy

; HU

: Hyd

roxy

urea

;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

e; M

ETRO

: Met

roni

dazo

le; M

ISO

: Mis

onid

azol

e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

ND

: Not

eno

ugh

data

to

dete

rmin

e; P

CB:

Pro

carb

azin

e;

PCN

U: P

iper

idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

RT; T

EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

eshi

va U

nive

rsity

on

10/1

7/13

For

pers

onal

use

onl

y.

Glioblastomamultiforme:areviewofwherewehavebeenandwherewearegoing

1068 ExpertOpin.Investig.Drugs(2009) 18(8)

RC

T,y

ear

stu

dy

star

ted

[re

f]‡

Trea

tmen

tar

ms

(n)§

MA

(y)

%G

BM

Sig

nifi

can

to

utc

om

es

EORT

C, 1

973

[122

]RT

(59)

,RT

+C

CN

U (5

2)Y

ND

69RT

+C

CN

U in

crea

sed

MST

fro

m 1

0 –

14m

com

pare

d w

ith R

T al

one.

Cha

ng, 1

974

[89]

RT (1

48),

RT+

boos

ter

RT (1

05),

RT+

BCN

U (1

65),

RT+

MeC

CN

U+

DTI

C (1

36)

Y55

% w

ere

40

– 5

966

– 7

1Pr

elim

inar

y re

port

of

stud

y. N

o si

gnifi

cant

diff

eren

ce b

etw

een

cont

rol a

nd t

reat

men

t ar

ms

in M

ST

Hat

levo

ll, 1

974

[123

]8

arm

s te

stin

g RT

40

Gy,

RT

50

Gy,

MIS

O, C

CN

U;

cont

rol w

as R

T al

one

(2

44 t

otal

)

Y51

– 5

6N

DN

o si

gnifi

cant

diff

eren

ce in

MST

bet

wee

n al

l arm

s

Urt

asan

, 197

4 [1

24]

RT (1

5),

RT+

high

-dos

e m

etro

nida

zole

NN

D10

0M

etro

nida

zole

incr

ease

d M

ST f

rom

3.5

– 6

m, m

akin

g tu

mor

ce

lls m

ore

radi

osen

sitiv

e

Kris

tians

en, 1

974

[95]

Con

serv

ativ

e ca

re (3

8),

RT+

plac

ebo

(35)

,RT

+bl

eom

ycin

(45)

YN

DN

DRT

impr

oved

MST

; no

sign

ifica

nt in

crea

se in

MST

with

ble

omyc

in

Eyre

, 197

4 [1

25]

RT+

CC

NU

(56)

,RT

+C

CN

U+

PCB

(59)

YN

D75

No

sign

ifica

nt in

crea

se in

MST

with

PC

B

Nel

son,

197

4 [1

26]

RT 6

0 G

y (1

41),

RT 6

0 G

y+10

boo

st (1

03),

RT 6

0 G

y+BC

NU

(156

),RT

44

Gy+

MeC

CN

U+

DTI

C (1

38)

NN

D72

– 7

7O

vera

ll, n

o si

gnifi

cant

diff

eren

ce w

hen

addi

ng R

T bo

ost,

BC

NU

, C

CN

U, o

r D

TIC

; 40-

to

60-y

-old

pat

ient

s ha

d in

crea

sed

2-y

surv

ival

fro

m 8

– 2

3% w

hen

BCN

U w

as a

dded

to

RT

Blee

hen,

197

6 [1

27]

RT 5

6 G

y (2

0),

RT 4

4 G

y (1

8),

RT 4

4 G

y+M

ISO

(17)

N50

– 5

831

– 3

5N

o si

gnifi

cant

incr

ease

in M

ST w

ith M

ISO

rad

iose

nsiti

zer

Urt

asun

, 197

6 [1

28]

RT (1

9),

HRT

+ m

etro

nida

zole

(17)

,H

RT+

MIS

O (2

3)

N58

75N

o si

gnifi

cant

incr

ease

in M

ST w

ith m

etro

nida

zole

or

MIS

O

radi

osen

sitiz

er

Not

e: R

CTs

are

list

ed c

hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

ion,

bre

akdo

wn

of c

ontr

ol v

ersu

s tr

eatm

ent

arm

s, y

ear

stud

y be

gan,

pop

ulat

ion

size

, tre

atm

ents

, mul

ticen

ter

stat

us, a

vera

ge a

ge o

f

part

icip

ants

, per

cent

age

of G

BM p

artic

ipan

ts, t

reat

men

ts, a

nd r

esul

ts.

*Tak

en f

rom

sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

Con

trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

DTI

C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

%G

BM: R

ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

grou

p; G

y: G

ray;

HD

-MP:

Hig

h-do

se m

ethy

lpre

dnis

olon

e; H

RT: H

yper

frac

tiona

ted

RT; H

SVTK

/G: H

erpe

s si

mpl

ex v

irus

type

1 t

hym

idin

e ki

nase

and

gan

cicl

ovir

gene

the

rapy

; HU

: Hyd

roxy

urea

;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

e; M

ETRO

: Met

roni

dazo

le; M

ISO

: Mis

onid

azol

e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

ND

: Not

eno

ugh

data

to

dete

rmin

e; P

CB:

Pro

carb

azin

e;

PCN

U: P

iper

idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

RT; T

EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Tab

le2

.Su

mm

ary

of

allP

has

eIII

ran

do

miz

edc

linic

alt

rial

san

do

utc

om

esin

glio

bla

sto

ma*

(co

nti

nu

ed).

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

eshi

va U

nive

rsity

on

10/1

7/13

For

pers

onal

use

onl

y.

Adamson,Kanu,Mehta,Di,Lin,Mattox&Bigner

ExpertOpin.Investig.Drugs(2009) 18(8) 1069

RC

T,y

ear

stu

dy

star

ted

[re

f]‡

Trea

tmen

tar

ms

(n)§

MA

(y)

%G

BM

Sig

nifi

can

to

utc

om

es

Gre

en, 1

976

[129

]RT

+BC

NU

(147

),RT

+H

D-M

P (1

56),

RT+

PCB

(153

)RT

+BN

CU

+H

D-M

P (1

53)

YN

D87

The

addi

tion

of B

CN

U o

r PC

B in

crea

sed

MST

fro

m

9m t

o 11

m. H

D-M

P di

d no

t in

crea

se M

ST

Payn

e, 1

977

[130

]RT

(79)

,SR

T (7

8)N

ND

ND

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith h

yper

frac

tiona

ted

RT

Grif

fin, 1

977

[131

]RT

50

Gy+

phot

onbo

ost

(83)

,RT

50

Gy+

neut

ron

Boos

t (8

3)

YN

DN

DN

o si

gnifi

cant

diff

eren

ce in

MST

bet

wee

n ne

utro

n or

pho

ton

boos

t

Eyre

, 197

7 [1

32]

RT+

BCN

U (8

2),

RT+

PCB

(83)

,RT

+D

TIC

(78)

Y55

84BC

NU

or

DTI

C in

crea

sed

MST

to

11m

whe

n co

mpa

red

to P

CB

(7m

)

Afr

a, 1

978

[133

]RT

(32)

,RT

+D

BD (2

8),

RT+

DBD

+C

CN

U (3

1)

YN

D63

DBD

incr

ease

d M

ST f

rom

9m

– 1

3m w

hen

com

pare

d to

RT

alon

e.

CC

NU

add

ed n

o si

gnifi

cant

ben

efit

over

DBD

Shin

, 197

8 [1

34]

RT+

CC

NU

(34)

,SR

T+C

CN

U (3

5)N

54N

DSR

T (3

fra

ctio

ns/d

ay) i

mpr

oved

MST

fro

m 9

– 1

3m

Deu

tsch

, 197

8 [1

35]

RT+

BCN

U (1

52),

RT+

stre

ptoz

ocin

(146

),H

RT+

BC

NU

(154

),RT

+M

ISO

pre

-BC

NU

(151

)

YN

D86

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith M

ISO

or

HRT

MRC

, 197

9 [1

36]

RT+

Plac

ebo

(196

),RT

+M

ISO

(188

)Y

ND

58N

o si

gnifi

cant

diff

eren

ce in

MST

with

MIS

O

Nel

son,

197

9 [1

37]

RT+

BCN

U (1

46),

RT+

BCN

U+

MIS

O (1

47)

YN

D83

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith M

ISO

Taka

kura

, 198

0 [1

38]

RT (3

7),

RT+

AC

NU

(40)

YN

D58

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith A

CN

U

Not

e: R

CTs

are

list

ed c

hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

ion,

bre

akdo

wn

of c

ontr

ol v

ersu

s tr

eatm

ent

arm

s, y

ear

stud

y be

gan,

pop

ulat

ion

size

, tre

atm

ents

, mul

ticen

ter

stat

us, a

vera

ge a

ge o

f

part

icip

ants

, per

cent

age

of G

BM p

artic

ipan

ts, t

reat

men

ts, a

nd r

esul

ts.

*Tak

en f

rom

sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

Con

trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

DTI

C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

%G

BM: R

ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

grou

p; G

y: G

ray;

HD

-MP:

Hig

h-do

se m

ethy

lpre

dnis

olon

e; H

RT: H

yper

frac

tiona

ted

RT; H

SVTK

/G: H

erpe

s si

mpl

ex v

irus

type

1 t

hym

idin

e ki

nase

and

gan

cicl

ovir

gene

the

rapy

; HU

: Hyd

roxy

urea

;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

e; M

ETRO

: Met

roni

dazo

le; M

ISO

: Mis

onid

azol

e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

ND

: Not

eno

ugh

data

to

dete

rmin

e; P

CB:

Pro

carb

azin

e;

PCN

U: P

iper

idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

RT; T

EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Tab

le2

.Su

mm

ary

of

allP

has

eIII

ran

do

miz

edc

linic

alt

rial

san

do

utc

om

esin

glio

bla

sto

ma*

(co

nti

nu

ed).

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

eshi

va U

nive

rsity

on

10/1

7/13

For

pers

onal

use

onl

y.

Glioblastomamultiforme:areviewofwherewehavebeenandwherewearegoing

1070 ExpertOpin.Investig.Drugs(2009) 18(8)

RC

T,y

ear

stu

dy

star

ted

[re

f]‡

Trea

tmen

tar

ms

(n)§

MA

(y)

%G

BM

Sig

nifi

can

to

utc

om

es

Shap

iro, 1

980

[139

]RT

+BC

NU

(114

),RT

+BC

NU

+PC

B (1

76),

RT+

BCN

U+

HU

+V

M26

(168

)

YN

D80

Con

ed-d

own

RT a

s ef

fect

ive

as w

hole

bra

in R

T. P

CB,

HU

, VM

26

did

not

impr

ove

MST

Ellio

tt, 1

980

[140

]RT

+BC

NU

(114

),RT

+D

BD (1

15)

YN

D63

No

sign

ifica

nt d

iffer

ence

in M

ST b

etw

een

BCN

U a

nd D

BD

EORT

C, p

re-1

981

[141

]RT

(55)

,RT

+C

CN

U+

VM

26 e

arly

(61)

RT+

CC

NU

+V

M26

late

(21)

Y39

% <

50

30N

o si

gnifi

cant

diff

eren

ce in

MST

bet

wee

n al

l arm

s

Mah

aley

, 198

1 [1

42]

RT+

BCN

U (2

5),

RT+

BCN

U+

PCB

(28)

,RT

+BC

NU

+H

U/P

CB+

VM

26 (2

8)

N53

.276

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith a

dditi

on o

f PC

B, H

U, o

r V

M26

Ludg

ate,

198

1 [1

43]

RT (3

4),

SRT

(42)

N55

.5N

DEa

rly b

enefi

t (M

ST in

crea

sed

from

7.4

m –

10.

6m),

but

no la

te

bene

fit

Sand

berg

-Wol

lhei

m, 1

981

[144

]PC

V (7

1),

RT+

PCV

(68)

NN

D47

For p

atie

nts

< 5

0y o

ld, R

T+PC

V in

crea

sed

MST

from

10.

8m –

15.

2m

whe

n co

mpa

red

to P

CV

alo

ne

Levi

n, 1

977

[145

]RT

/HU

+BC

NU

(66)

,RT

/HU

+PC

V (6

7)Y

41 –

57

44 –

46

No

sign

ifica

nt d

iffer

ence

in M

ST b

etw

een

arm

s fo

r G

BM

Blee

hen,

198

3 [1

46]

RT 4

5 G

y (1

56),

RT 6

0 G

y (3

18)

YN

D67

60 G

y in

crea

sed

MST

fro

m 9

– 1

2m w

hen

com

pare

d w

ith 4

5 G

y

Shap

iro, 1

983

[147

]RT

+In

trav

enou

s BC

NU

(126

),RT

+In

tra-

arte

rial B

CN

U (1

53)

YN

D75

MST

dec

reas

ed w

ith in

tra-

arte

rial B

CN

U w

ith s

igni

fican

t to

xici

ties

Din

apol

i, 19

85 [1

48]

RT+

BCN

U (1

66),

RT+

PCN

U (1

68)

YN

D71

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith P

CN

U, w

ith w

orse

to

xici

ties

MRC

, 198

5 [1

49]

RT (3

39),

RT+

PCV

(335

)Y

ND

81N

o si

gnifi

cant

diff

eren

ce in

MST

with

PC

V

Selk

er, 1

987

[150

]RT

+BC

NU

(137

)RT

+IR

T bo

ost+

BCN

U (1

33)

YN

D85

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith IR

T bo

ost

Not

e: R

CTs

are

list

ed c

hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

ion,

bre

akdo

wn

of c

ontr

ol v

ersu

s tr

eatm

ent

arm

s, y

ear

stud

y be

gan,

pop

ulat

ion

size

, tre

atm

ents

, mul

ticen

ter

stat

us, a

vera

ge a

ge o

f

part

icip

ants

, per

cent

age

of G

BM p

artic

ipan

ts, t

reat

men

ts, a

nd r

esul

ts.

*Tak

en f

rom

sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

Con

trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

DTI

C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

%G

BM: R

ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

grou

p; G

y: G

ray;

HD

-MP:

Hig

h-do

se m

ethy

lpre

dnis

olon

e; H

RT: H

yper

frac

tiona

ted

RT; H

SVTK

/G: H

erpe

s si

mpl

ex v

irus

type

1 t

hym

idin

e ki

nase

and

gan

cicl

ovir

gene

the

rapy

; HU

: Hyd

roxy

urea

;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

e; M

ETRO

: Met

roni

dazo

le; M

ISO

: Mis

onid

azol

e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

ND

: Not

eno

ugh

data

to

dete

rmin

e; P

CB:

Pro

carb

azin

e;

PCN

U: P

iper

idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

RT; T

EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Tab

le2

.Su

mm

ary

of

allP

has

eIII

ran

do

miz

edc

linic

alt

rial

san

do

utc

om

esin

glio

bla

sto

ma*

(co

nti

nu

ed).

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

eshi

va U

nive

rsity

on

10/1

7/13

For

pers

onal

use

onl

y.

Adamson,Kanu,Mehta,Di,Lin,Mattox&Bigner

ExpertOpin.Investig.Drugs(2009) 18(8) 1071

RC

T,y

ear

stu

dy

star

ted

[re

f]‡

Trea

tmen

tar

ms

(n)§

MA

(y)

%G

BM

Sig

nifi

can

to

utc

om

es

Troj

anow

ski,

pre1

988

[151

]RT

(104

),RT

+C

CN

U (9

4)Y

53%

≤ 5

041

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith C

CN

U

Pick

les,

198

8 [1

52]

RT (

41)

Pion

RT

(40)

YN

D83

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith p

ion

RT

Hild

ebra

nd, 1

989

[153

]RT

(134

),RT

+D

BD+

BCN

U (1

35)

YN

D77

DBD

+BC

NU

incr

ease

d M

ST f

rom

10m

– 1

3m w

hen

com

pare

d w

ith R

T al

one

Val

tone

n, 1

992

[154

]Pl

aceb

o im

plan

t+RT

(16)

,G

liade

l im

plan

t+RT

(16)

YN

D85

Glia

del s

igni

fican

tly in

crea

sed

MST

fro

m 9

.2m

to

13.4

m

Wel

ler,

199

4 [1

55]

RT+

AC

NU

+V

M26

(183

),RT

+A

NC

U+

Ara

-C (1

79)

YN

D83

No

signi

fican

t diff

eren

ce in

MST

bet

wee

n V

M26

and

Ara

-C

Buck

ner,

199

4 [1

56]

RT+

BCN

U (9

8),

ART

+BC

NU

(103

),RT

+BC

NU

+ci

spla

tin (1

00),

ART

+BC

NU

+ci

spla

tin (1

00)

Y55

– 5

695

– 9

9N

o di

ffer

ence

in M

ST b

etw

een

cisp

latin

and

con

trol

arm

s.

Cis

plat

in p

rodu

ced

mor

e to

xici

ty. R

T an

d A

RT p

rodu

ced

sim

ilar

toxi

city

Levi

n, 1

996

[157

]RT

+pl

aceb

o (7

9),

RT+

Mar

imas

tat

(83)

Y57

– 5

895

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith m

arim

asta

t

Rain

ov, 1

996

[158

]RT

(124

),RT

+H

SVTK

/G (1

24)

Y59

96N

o si

gnifi

cant

diff

eren

ce in

MST

with

gen

e th

erap

y

Gro

ssm

an, 1

996

[159

]RT

+BC

NU

(110

),BC

NU

+ci

spla

tin p

re-R

T (1

09)

YN

D99

No

sign

ifica

nt d

iffer

ence

in M

ST w

ith c

ispl

atin

giv

en b

efor

e RT

Wes

tpha

l, 19

97 [8

8]Pl

aceb

o im

plan

t+RT

(120

),G

liade

l im

plan

t+RT

(120

)Y

ND

99G

liade

l inc

reas

ed M

ST f

rom

11.

6m –

13.

9m

Will

ems,

199

9 [1

60]

Surg

ery

(36)

,Su

rger

y+ne

uron

avig

atio

n (2

6)N

6069

No

diff

eren

ce in

am

ount

of

rese

ctio

n or

MST

Com

bs, 1

999

[161

]RT

+50

mg/

m T

EMO

(123

),RT

+75

mg/

m T

EMO

(37)

N57

– 6

110

0N

o di

ffer

ence

in o

vera

ll su

rviv

al w

ith lo

wer

-dos

e TE

MO

Not

e: R

CTs

are

list

ed c

hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

ion,

bre

akdo

wn

of c

ontr

ol v

ersu

s tr

eatm

ent

arm

s, y

ear

stud

y be

gan,

pop

ulat

ion

size

, tre

atm

ents

, mul

ticen

ter

stat

us, a

vera

ge a

ge o

f

part

icip

ants

, per

cent

age

of G

BM p

artic

ipan

ts, t

reat

men

ts, a

nd r

esul

ts.

*Tak

en f

rom

sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

Con

trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

DTI

C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

%G

BM: R

ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

grou

p; G

y: G

ray;

HD

-MP:

Hig

h-do

se m

ethy

lpre

dnis

olon

e; H

RT: H

yper

frac

tiona

ted

RT; H

SVTK

/G: H

erpe

s si

mpl

ex v

irus

type

1 t

hym

idin

e ki

nase

and

gan

cicl

ovir

gene

the

rapy

; HU

: Hyd

roxy

urea

;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

e; M

ETRO

: Met

roni

dazo

le; M

ISO

: Mis

onid

azol

e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

ND

: Not

eno

ugh

data

to

dete

rmin

e; P

CB:

Pro

carb

azin

e;

PCN

U: P

iper

idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

RT; T

EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Tab

le2

.Su

mm

ary

of

allP

has

eIII

ran

do

miz

edc

linic

alt

rial

san

do

utc

om

esin

glio

bla

sto

ma*

(co

nti

nu

ed).

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

eshi

va U

nive

rsity

on

10/1

7/13

For

pers

onal

use

onl

y.

Glioblastomamultiforme:areviewofwherewehavebeenandwherewearegoing

1072 ExpertOpin.Investig.Drugs(2009) 18(8)

RC

T,y

ear

stu

dy

star

ted

[re

f]‡

Trea

tmen

tar

ms

(n)§

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est

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pson

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g. S

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oda,

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6 [1

67]

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0),

RT+

125 I

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FR a

ntib

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(8)

N47

– 5

272

No

diff

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ce in

sur

viva

l with

125 I

-EG

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ntib

ody

Not

e: R

CTs

are

list

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hron

olog

ical

ly a

nd in

clud

e au

thor

with

yea

r of

pub

licat

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bre

akdo

wn

of c

ontr

ol v

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s tr

eatm

ent

arm

s, y

ear

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y be

gan,

pop

ulat

ion

size

, tre

atm

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, mul

ticen

ter

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us, a

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f

part

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, per

cent

age

of G

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reat

men

ts, a

nd r

esul

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sea

rch

of C

ochr

ane

Cen

tral

Reg

iste

r of

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trol

led

Tria

ls (C

ENTR

AL)

. Sea

rch

term

s in

clud

ed ‘g

liobl

asto

ma(

s)’,

‘hig

h-gr

ade

glio

ma(

s)’,

and

‘mal

igna

nt g

liom

a(s)

’. Re

fere

nces

of

sele

cted

stu

dies

wer

e us

ed t

o

iden

tify

addi

tiona

l tria

ls.

‡ Mos

t st

udie

s re

port

ed s

tart

of

patie

nt a

ccru

al. F

or t

hose

tha

t di

d no

t, t

he p

ublic

atio

n ye

ar w

as s

tate

d.§ T

he fi

rst

liste

d tr

eatm

ent

arm

is t

he c

ontr

ol a

rm f

or t

he s

tudy

.

5-A

LA: 5

-Am

inol

evul

inac

aci

d; A

: Age

(ran

ge in

mea

n ag

e fo

r ea

ch t

reat

men

t gr

oup)

; AC

NU

: Nim

ustin

e; A

RT: A

ccel

erat

ed R

T; B

CN

U: C

arm

ustin

e; C

CN

U: L

omus

tine;

CED

/Ch8

1C6:

Con

vect

ion-

enha

nced

del

iver

y of

hum

an-m

urin

e ch

imer

ic m

onoc

lona

l ant

itena

scin

ant

ibod

y C

h81C

6; D

BD: D

ibro

mod

ulci

tol;

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C: D

acar

bazi

ne; D

TI-N

N: D

iffus

ion

tens

or im

agin

g-ba

sed

func

tiona

l neu

rona

viga

tion;

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ange

in p

erce

ntag

e of

GBM

for

each

tre

atm

ent

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y: G

ray;

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h-do

se m

ethy

lpre

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RT: H

yper

frac

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ex v

irus

type

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gene

the

rapy

; HU

: Hyd

roxy

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;

IRT:

Inte

rstit

ial R

T; m

: Mon

ths;

M: M

ultic

ente

r; M

eCC

NU

: Sem

ustin

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ETRO

: Met

roni

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le; M

ISO

: Mis

onid

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e; M

ST: M

edia

n su

rviv

al t

ime;

n: N

umbe

r pe

r gr

oup;

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: Not

eno

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data

to

dete

rmin

e; P

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Pro

carb

azin

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idin

e ni

tros

oure

a; P

CV

: Pro

carb

azin

e/vi

ncris

tine/

lom

ustin

e; R

T: E

xter

nal b

eam

rad

ioth

erap

y; S

RT: S

uper

frac

tiona

ted

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EMO

: Tem

ozol

omid

e; V

M26

: Ten

ipos

ide;

y: Y

ear.

Tab

le2

.Su

mm

ary

of

allP

has

eIII

ran

do

miz

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linic

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san

do

utc

om

esin

glio

bla

sto

ma*

(co

nti

nu

ed).

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ExpertOpin.Investig.Drugs(2009) 18(8) 1073

partially. Yet maximal cytoreduction appears to improve survival only in the short term. As seen in a recent meta-analysis, 2-year disease-free survival is unchanged in patients who receive maximal cytoreductive surgery versus biopsy alone [15]. Patients who undergo surgery at high-volume academic centers appear to have an advantage, as mortality at these centers is half (2.5%) of that seen at low-volume centers (4.9%) [94].

RT has also been shown to add several months to survival, and has become part of the standard of care. Currently, postoperative fractionated external-beam radiotherapy is rou-tine. It is administered as 60 Gy in 30 fractions over a period of about 6 weeks to a target volume defined as a 2- to 3-cm ring of tissue beyond the contrast-enhancing rim of tumor seen on the preoperative MRI or CT scan. All enhancing tumor is ideally resected and not visible on postoperative neuroimaging. RT should not be started before 2 weeks after surgery, to allow for adequate wound healing. Phase III RCTs have shown that RT can prolong survival after surgery to 9 – 10 months, doubling the 4 – 5 months’ survival of patients who receive only supportive care after surgery [95,96]. Whole-brain RT is typically used for multifocal GBM, such as gliomatosis cerebri.

Chemotherapy has seen the longest, most varied, and most disappointing history in laboratory and clinical research, with numerous RCTs dating to the 1970s (Table 2). Meta-analyses looking at various heterogeneous chemotherapy regimens show an overall survival benefit of an additional 1 – 2 months. Therefore, in combination with surgery and RT, chemotherapy provides an overall median survival of about 14 months. However, this probably includes significant selection biases and improved outcomes for patients involved in clinical trials [15,97]. Despite this long history, only two agents have made their way into standard-of-care treatments for newly diagnosed and recurrent GBM: Gliadel and temo-zolomide (TMZ), both of which separately increase survival by about 2 months [88,98,99]. TMZ is an imidazotetrazine derivative of the alkylating agent dacarbazine. It gets con-verted in the systemic circulation at physiologic pH to the active compound monomethyl triazone imidazole carboxam-ide (MTIC). It exhibits schedule-dependent antineoplastic activity by interfering with DNA replication. Like most prior GBM chemotherapies, it acts nonspecifically on rap-idly dividing cells, but has the benefit of some crossing of the blood–brain barrier and much less toxicity. TMZ should be administered concomitantly with RT at 75 mg/m2 daily followed by 200 mg/m2 for 5 days every 4 weeks for a total of 6 months [99]. Patients with methylation (and therefore silencing of gene expression) of MGMT that confers resis-tance to alkylating agents respond better to TMZ [100]. The efficacy of the combination of BCNU and TMZ has not been established, nor has any RCT consistently shown any benefit to pre-RT chemotherapy. Antiangiogenic agents have shown the most success of recently explored chemotherapies, with bevacizumab recently obtaining FDA approval for use in GBM.

Recurrent tumor, which happens virtually 100% of the time, is clearly more difficult to treat. These patients may be considered for cytoreductive surgery again if they have a good KPS and a biopsy has ruled out radiation necrosis, which can easily mimic recurrent tumor. Numerous studies have looked at recurrent GBM (Table 2), but no standard of care for recurrent tumor has been established. Gliadel may be considered. Based on the available evidence, most neuro-oncologists recommend TMZ re-challenge in patients who did not progress while on TMZ or another nitrosourea-based chemotherapy. RT is usually not an option, since most patients will have undergone the full course during initial presentation. As seen with newly diag-nosed GBM, patients with recurrent tumor should also be considered for clinical trials, due to the benefits associated with participation.

6. ‘Wherewearegoing’

Despite our tremendous breadth and depth of understanding in the oncogenomics and molecular biology of GBM, the overwhelming majority of successful preclinical therapies have failed to provide meaningful results at the clinical stage of testing. There are several possible reasons for our current treatment failures. However, significant knowledge gained from these, together with new insight into the molecular biology of GBM, has provided new directions for where we are going with future therapeutic studies. In addition to numerous surgical tools and radiation strategies under study, current chemotherapeutic strategies under study cover a broad array of treatments and approaches (Table 3 and Figure 2). The most common types of chemotherapies under investigation include targeted molecular therapies, antiangiogenic therapies, immunotherapies, gene therapies, radiation-enhancement therapies, and drugs to overcome resistance (Table 3 and Figure 2) [101-104].

One well-known reason for failure of the standard chemotherapy in use today, TMZ, is the presence of DNA repair enzymes, namely MGMT as described above. Techniques for circumventing this DNA protective enzyme may make TMZ more effective and are under active investigation (Table 3). Dose-intensive TMZ to quickly deplete MGMT, combinations of TMZ with MGMT inhibitors (e.g., O6-benzylguanine), or combinations of TMZ with other DNA repair enzyme inhibitors (e.g., poly-ADP-ribose-polymerase) are being studied [105].

As mentioned above, there appear to be multiple, redundant signaling pathways in GBM. Therefore, the upstream location of targets (e.g., growth factor receptors) makes the drugs that target them susceptible to downstream resistance due to other factors driving the pathway of interest. This implies that combination therapies may be required to significantly target a specific pathway, or a combination of important pathways [106]. Recent clinical trials have already begun exploring combination therapies. For example, a Phase II

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Table3.Currentclinicaltrialsforinvestigationaldrugsinglioblastoma.

Typeoftreatmentstrategyandtarget Investigationalagents

Small molecule targeted therapies

AKT inhibitor Perifosine

EGF RTK inhibitor Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab, cetuximab, AEE788

Growth factor inhibitor Leflunomide, suramin

FTI inhibitor Tipifarnib, lonafarnib

HDAC inhibitor Vorinostat, depsipeptide, panobinostat, romidepsin

HSP90 inhibitor AT13387

LDL receptor peptide ANG1005 (taxane derivative targets LDL receptors)

Met inhibitor XL184

MMP inhibitor Prinomastat

Microtubule disruption CYT997, MPC-6827, epothilones

mTOR inhibitor Everolimus, sirolimus, temsirolimus, deforolimus, rapamycin

PDGF RTK inhibitor Dasatinib, imatinib, tandutinib, pazopanib

PI3K inhibitor BEZ235, XL765

PKCβ STK inhibitor Enzastaurin

Proteosome inhibitor Bortezomib

Raf inhibitor Sorafenib

Ras inhibitor TLN-4601

Sp1 inhibitor Terameprocol

Src TK inhibitor Dasatinib

TGFβ inhibitor AP12009 (antisense)

Topoisomerase inhibitors RTA744, etoposide, topotecan, irinotecan, AQ4N, edotecarin, rubitecan, pyrazoloacridine, karenitecin, gimatecan

VEGF RTK inhibitor PTK787, semaxanib

Others 131I-TM601 (scorpion venom peptide), CC-8490

Antiangiogenic therapies

Anti-αvβ5 integrins Cilengitide, ATN-161

Anti-hepatocyte GF AMG-102

Anti-VEGF Bevacizumab, aflibercept (VEGF-Trap)

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

Others Thalidomide, lenalidomide, atrasentan (endothelin- A receptor antagonist), ABT-510

Immunotherapies

Bispecific antibodies MDX447 (EGFR and CD64)

Cytokine-mediated Cintredekin besudotox (IL13-PE38QQR), PRX321 (IL-PE), NBI-3001 (IL4- PE38KDEL), aldesleukin (IL2 analog)

Dendritic cell vaccines DC pulsed with tumor cell lysates (DCVax) EGFRvIII peptide (CDX-110), tumor stem cell mRNA

Note: Summary of 498 currently active clinical trials for glioblastoma in the United States (clinicaltrials.gov).

CpG ODN: Cytosine-guanine island oligodeoxynucleotides; DC: Dendritic cells; EGF: Epidermal growth factor; FTI: Farnesyl transferase inhibitors; GF: Growth

factor; HDAC: Histone deacetylase; HSP: Heat shock protein; IL: Interleukin; LDL: Low-density lipoprotein; MGMT: Methylguanine methyltransferase; MMP: Matrix

metalloproteinase; PARP: Poly-(ADP ribose)-polymerase; PDGF: Platelet derived growth factor; PE: Pseudomonas exotoxin; RTK: Receptor tyrosine kinase;

STK: Serine-threonine kinase; TK: Tyrosine kinase; TMZ: Temozolomide; VEGF: Vascular endothelial growth factor.

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trial of an antiangiogenic antibody, bevacizumab, combined with a topoisomerase I small molecule inhibitor, irinotecan, showed efficacy in recurrent GBM [107]. Understandably, older studies focused on proteins overexpressed on the surface of GBM cells as promising targets. Antibodies directed at EGFR and its mutated variants have been studied for many years, but they have not quickly translated into effective therapies. More work is being done. The more recent eluci-dation of the aberrant signaling pathways and their redundant, cross-talking factors (e.g., mTOR) have now moved a signifi-cant amount of focus toward studying small molecules that can directly target these downstream factors (Table 3). Numerous commonly studied signaling factors are now being targeted by investigational drugs in modern clinical trials (Figure 2). Therapies directed at unique proteins are typically small molecule inhibitors. These agents target factors such as Akt (perifosine), EGFR (erlotinib), farnesyl transferase (lonafarnib), histone deacetylase (vorinostat), heat shock proteins (AT13387), Met (XL184), mTOR (sirolimus), PI3K (BEZ235), PKCβ (enzastaurin), PDGFR (imatinib), proteasomes (bortezomib), Raf (sorafenib), Src (dasatinib), and TGF-β (AP12009).

Many of these are in trials of combination therapies. This approach offers the advantage of remarkable specificity, reduced toxicity, and applicability to other cancers with similar aberrant signaling cascades.

Recent clinical trials have shown great promise with antiangiogenic therapies in this highly vascular tumor. Current investigational antiangiogenic therapies consist of antibodies directed toward factors such as αvβ5 integrins (cilengitide), hepatocyte growth factor (AMG-102), VEGF (bevacizumab), and VEGFR (sunitinib). Because of its clinical success, beva-cizumab will probably be the next antiangiogenic agent approved by the FDA for recurrent GBM [107-110]. Some of these therapies have the advantage of directly targeting tumor vasculature, as well as tumor cells directly. The pri-mary concern of these therapies is the possible increased risk of intracranial hemorrhagic complications. Current studies (Table 3) will help determine the efficacy and risk profile of these exciting therapies.

As alluded to above, we now know that the altered immune environment in GBM probably contributes to tumor progression and hampers therapies. Numerous exciting and

Table3.Currentclinicaltrialsforinvestigationaldrugsinglioblastoma.

Typeoftreatmentstrategyandtarget Investigationalagents

Immunostimulatory GM-CSF + PEP-3-KLH (EGFRvIII peptide), Lyphokine-activated killer cells, CpG ODN (activate dendritic and B cells), autologous tumor cell vaccine, Poly ICLC (toll-like receptor 3 ligand), vitespan (patient-specific HSPgp96 vaccine), Immuncell-LC (activated T cells)

Immunotoxin Transferrin-CRM107 (transferrin + diphtheria), TP-38 (TGFα + PE)

Radiolabeled antibodies 131I-anti-tenascin antibody (81c6), Cotara (TNT-1/B, 131I–labeled tumor necrosis antigen antibody), Astatine At211-anti-tenascin antibody (81c6)

Gene therapies

Adenovirus vector Recombinant adenovirus-hIFNb, ADV-TK (ADV-HSV thymidine kinase) + valacyclovir, ADV-p53 (SCH-58500), Ad5CMV-p53

Cytokine genes IFNb gene transfer

Oncolytic viruses G207 (herpes simplex virus I)

Reovirus mediated Reolysin (targets Ras-activated cells)

Drugs for TMZ resistance

Dose-dense TMZ TMZ

MGMT inhibitors O6-benzylguanine

PARP inhibitors BSI-201, ABT-888

Note: Summary of 498 currently active clinical trials for glioblastoma in the United States (clinicaltrials.gov).

CpG ODN: Cytosine-guanine island oligodeoxynucleotides; DC: Dendritic cells; EGF: Epidermal growth factor; FTI: Farnesyl transferase inhibitors; GF: Growth

factor; HDAC: Histone deacetylase; HSP: Heat shock protein; IL: Interleukin; LDL: Low-density lipoprotein; MGMT: Methylguanine methyltransferase; MMP: Matrix

metalloproteinase; PARP: Poly-(ADP ribose)-polymerase; PDGF: Platelet derived growth factor; PE: Pseudomonas exotoxin; RTK: Receptor tyrosine kinase;

STK: Serine-threonine kinase; TK: Tyrosine kinase; TMZ: Temozolomide; VEGF: Vascular endothelial growth factor.

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varied investigational immunotherapies for GBM are now being pursued, including passive, active, and adoptive immu-notherapeutic approaches (Table 3). Passive immunotherapy involves administering antibodies or toxins to patients without specifically inducing or expanding a host antitumor response. Examples of antibodies currently under study include iodine 131-labeled antitenascin antibody (also known as 81C6), astatine 211-labeled antitenascin antibody, and the bispecific anti-EGFR and anti-CD64 antibody. Immunotoxin therapies include transferrin-CRM107 (transferrin conjugated with diphtheria toxin) and TP-38 (TGF-α conjugated with Pseudomonas exotoxin). These passive immunotherapies all target proteins overexpressed on the surface of glioma cells. TP-38 represents an elegant example of molecular engineering. This immunotoxin is a recombinant chimeric protein composed of the EGFR binding ligand, TGF-α and a genetically engineered Pseudomonas exotoxin. Once this pro-tein binds cells expressing EGFR, a domain of the exotoxin undergoes proteolytic cleavage and mediates translocation of the carboxyl terminal toxin into the cytosol. Another domain of the exotoxin contains an adenosine 5′-diphosphate (ADP) ribosylating activity that inactivates elongation factor 2, resulting in the death of the cell. In active immunotherapy, the tumor-bearing host is immunized with a ‘vaccine’ to expand an antitumor immune response in vivo, whereas adoptive immunotherapy employs the ex vivo expansion of effector cells and return of these effectors to the tumor-bearing host. Examples of active immunotherapies include autologous tumor cell vaccines, vitespen (heat shock protein gp96 vaccine), and PEP-3-KLH (EGFRvIII peptide conjugated to immunostimulatory agent). Exciting adoptive immuno-therapy strategies include various dendritic cell vaccines. In these complex treatments, autologous dendritic cells are iso-lated from patients, pulsed with tumor-specific molecules (e.g., tumor-specific peptides [EGFRvIII], tumor cell lysates, tumor stem cell mRNA), expanded ex vivo, and then rein-troduced to the patient [111] This field of investigation has slowly moved from nonspecific immunostimulatory approaches toward efforts eliciting very specific immune responses against tumor antigens, either by use of active immunization (cancer vaccines) or adoptive transfer of tumor-specific effector cells or antibodies (adoptive immunotherapy) [112].

Gene therapies experienced a surge of interest in the 1990s as genomic research tools became more available and cheaper and the Human Genome Project approached com-pletion. Directly inhibiting the expression of oncogenes and normalizing the expression of tumor suppressor genes has always been very appealing; however, the appearance of gene therapy approaches in clinical trials has not kept pace with studies of small-molecule protein inhibitors or antiangio-genic drugs. Gene delivery mechanisms are still being opti-mized. Several viral vectors (herpes simplex, adenovirus, and poliovirus), nanoparticle constructs, expression plasmids, and liposomal preparations to deliver numerous genes into tumor cells are still under study. Of these strategies, adenoviral

vectors are the most commonly used in studies today to deliver suicide genes such as thymidine kinase, or tumor suppressor genes such as p53. Most recently, results of genetic studies indicate that the next era of RCTs in GBM is likely to focus on using extensive gene expression databases to better characterize these deadly tumors and design more efficacious targeted therapies.

A very exciting area of study in GBM, and indeed in all cancers, is tumor stem cell biology. Now that the existence of this special tumor cell population has been confirmed, additional studies are required to further our understanding of the biology of these cells. We do know that glioma stem cells (GSCs) appear to be remarkably resistant to current radio- and chemotherapies, probably due to genomic and proteomic profiles that differ from the larger non-GSC population. Future therapies will have to effectively attack this small population of cells in order to impact upon the disease outcome. This will clearly be a very exciting area of investigational drug design in the near future.

GBM universally recurs due to proliferation of cells that have migrated away from the tumor focus. Current therapies have significant difficulty targeting these cells. Surgical resec-tion and local chemotherapies (e.g., Gliadel wafers placed in the resection cavities) are unlikely to target migrated cells. Investigators are using agents such as D-aminolevulinic acid to fluorescently label tumor cells to help assist surgeons dur-ing resection [113]; however, strategies such as this are also unlikely to allow surgeons to remove all tumor cells that have migrated away. Convention enhanced delivery (CED) methods allow therapies to be infiltrated into localized areas of brain parenchyma, potentially as large as an entire cerebral hemisphere. Curative therapies will have to be able to cross the highly selective blood–brain barrier, infiltrate throughout the entire brain, and specifically attack migrating cells without harming surrounding normal brain. Our current knowledge of GBM suggests a progressive accumulation of genomic and proteomic changes. This is clearly evident in the multitude of differences between primary and secondary GBM. However, it is not unreasonable that the progressive nature of genomic instability of these tumors never stops. Successful therapies will have to work quickly and thoroughly; recurrent tumors may require re-evaluation for different therapies due to a new genomic and proteomic profile.

7. Conclusion

In summary, the current recommendations for therapy are that all newly diagnosed GBM patients should be initially considered for cytoreductive surgery (> 98%), concurrent TMZ/RT 2 – 6 weeks after surgery, and then TMZ for 6 months. Recurrent tumor patients with a good KPS should be considered for resection again, followed by TMZ or a nitrosourea, and RT if they did not previously receive the maximal tolerated dose. Bevacizumab is likely to be approved by the FDA for recurrent disease in the near future,

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and if so it will become part of standard care for recurrent disease. These patients may benefit from a judicious use of corticosteroids to alleviate mass effect due to vasogenic edema. These should be tapered off as quickly as possible, since increased doses are likely to be needed during surgery or RT. Patients experiencing seizures should receive appropriate antiepileptic drugs (AED), but these should be carefully considered, since enzyme-inducing AED can alter the efficacy of chemotherapies. Because of the benefits of clinical trials, all patients should be referred to academic centers with active clinical studies. Patients should be followed closely (every 2 months with imaging) for the late sequelae of these aggressive treatments, such as cognitive deficits, electrolyte abnormalities, and deep venous thrombosis. Fortunately, there is significant hope for future therapies. Numerous promising areas of clinical investigation are underway (Table 3 and Figure 2) in diverse areas. Promising active areas of clinical study include small molecular inhibitors (e.g., everolimus, which targets mTOR), antiangiogenesis agents (e.g., anti-VEGF antibodies), novel immunotherapeutic approaches (e.g., dendritic cell vaccines stimulated with tumor-specific antigens, peptide vaccinations), growth factor receptor targeting (e.g., radiolabeled anti-EGFRvIII antibodies), gene therapies, strategies to overcome drug resistance, and combination therapies for specific molecular targets (e.g., topoisomerase, mTOR, and kinase inhibitors). More and more studies are looking at pediatric patients as well, with recent studies suggesting that they may have their own unique genetic expression profiles and signaling pathways [114]. TMZ is being studied in several studies in combination with other cytotoxic or cytostatic agents to improve current treatment schedules, or in studies to explore mechanisms to overcome chemotherapy resistance. There is real hope that the near future will see more effective targeted therapies, perhaps even designed to meet the needs of individual patients.

Glioblastoma has a long history of clinical investigation that has shaped our current understanding of this fatal disease. In all of oncology, it remains a relatively uncommon tumor, but is the most common primary CNS tumor encountered. Even though the number of studies of this disease has grown almost exponentially, we are still awaiting breakthroughs that can extend survival beyond the typical 14 months. There are currently no common, easily identifiable etiologies or risk factors, except for ionizing radiation and inherited syndromes; however, a complete unraveling of the GBM genome may provide important clues in the near future. Because of the rapidity of its progression, GBM typically results in symptoms at presentation that lead to is radiographic and pathologic diagnosis. Histopathologic descriptions have remained unchanged for decades, but are likely to be com-plemented by relevant genetic alterations, e.g., MGMT methylation status, as we gain a better understanding of the oncogenomic events and signaling pathways unique to GBM. During the past 5 years, we have witnessed a new postoperative standard of care that includes concomitant RT

and TMZ. This will be improved upon with the current surge of investigational drugs.

8. Expertopinion

Glioblastoma remains one of the most common and most malignant primary CNS tumors in humans. It continues to be a largely histologically diagnosed disease, even though ample evidence demonstrates tremendous genomic and proteomic heterogeneity. From this thorough review of ‘where we have been’ and ‘where we are going,’ it is clear that an enormous degree of investigation has been devoted to this universally fatal disease. Unfortunately, almost half a cen-tury of investigation has not drastically altered survival. Evidence supports continuation of an initial attempt to achieve > 98% tumor resection. When not involving elo-quent cortex, we believe this should be an achievable goal of all neuro-oncology surgeons. RCTs have also proven that postsurgical concomitant RT and TMZ will increase survive by 2.5 months, up to about 14 months. Even though other chemotherapies, namely nitrosoureas, have shown similar marginal benefit, TMZ should be the first-line postsurgical chemotherapy because of its ease of administration, low toxicity profile, and proven benefit. Intraoperative place-ment of Gliadel when appropriate is also considered by some to be standard of care. Gliadel has been demonstrated in RCTs to show similar survival benefit as TMZ; however, the benefit of the combination of these two therapies is still unclear and needs further rigorous investigation. Despite these various therapies, the current outcome remains dismal for these patients. Therefore, all patients should be rou-tinely referred to institutions with active clinical trials, since this also provides survival benefit. Young age and high KPS continue to be the strongest positive predictors of survival; these factors should be taken into consideration during counseling, when referring patients for additional therapy, and when treating tumor recurrence. If possible, recurrence should be treated with resection and adjuvant TMZ. Appropriate care of these patients should involve a multi-disciplinary team: neurosurgeon, neuro-oncologist, and radiation oncologist. There should also be mechanisms for assisting these patients with quality-of-life issues as the disease progresses. Involvement in institutions with dedicated brain tumor centers can offer significant benefits to these patients, since these centers often have individuals dedicated to helping oncology patients with the long-term care issues that inevitably arise.

With the explosion in gene expression profiling, signaling pathway characterization, GSC identification, and immuno-modulation strategies in GBM that has occurred over the last decade, there is now a tremendous surge in clinical studies evaluating new agents. In the next 5 – 10 years, these will be the major areas of investigational drug studies for GBM: specific molecular targeting, antiangiogenic therapies, immunotherapies, gene therapies, drugs to overcome resistance,

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Declarationofinterest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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AffiliationCory Adamson†1,2 MD PhD MPH MHSc, Okezie O Kanu3 MD, Ankit I Mehta1 MD, Chunhui Di1 BS, Ningjing Lin4 MD, Austin K Mattox1 BS & Darell D Bigner1 MD PhD†Author for correspondence1Duke Medical Center, MSRB 1 Box 2624, Durham, NC 27712, USA Tel: +1 919 698 3152; Fax: +1 919 684 5483; E-mail: cory.adamson@duke.edu2Neurosurgery Section, Durham VA Medical Center, Durham, NC, USA3Lagos University Teaching Hospital, Lagos, Nigeria4Peking University School of Oncology, Beijing Cancer Hospital, Department of Oncology, Beijing, China

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