Modern Trends in Non-Surgical
Treatment of Brain Tumors
Essay Submitted For Partial Fulfillment of the Master Degree in
Neuropsychiatry
By
Hesham Mohammad Ibrahim El Adrousy
M.B., B.CH. (2004)
Supervised by
Prof. Dr. Mohammad Yasser Metwally
Professor of Neuropsychiatry (www.yassermetwally.com)
Faculty of Medicine - Ain Shams University
Dr. Amr Abdel Moniem Mohammad
Lecturer of Neuropsychiatry
Faculty of Medicine – Ain Shams University
Ain Shams University
Faculty of Medicine
2010
Click here to download the PDF version of this thesis
(http://profyasser.files.wordpress.com/2010/03/nstbt.pdf)
Contents

Acknowledgement ...……................................ I I

List of Figures ………………………….….…...... III

List of Tables ……………………… …..……….... V

Introduction …………………………… ………….. 1

Aim of The Work ……………………………..…... 8

Review of Literature:
- Chapter 1: Molecular Pathogenesis of Brain Tumors ............ 9
- Chapter 2: Targeting Critical Points .................................... 31
- Chapter 3: Immunotherapy................................................. 47
- Chapter 4: Anti-angiogenic Therapy ................................... 63
- Chapter 5: Stereotactic Radiosurgery ................................. 81
- Chapter 6: Chemotherapy .................................................. 97
- Chapter 7: Endocrinal Therapy.......................................... 111
- Chapter 8: Gene and Viral Therapies ................................. 129

Discussion .................................................................145

Summary ................................................................... 161

Recommendations .................................................. 165

References ................................................................ 167

Arabic Summary ...................................................... 213
I
Acknowledgement
First and foremost, thanks to God to whom I owe my
self, existence and life .
Words are not enough to express my deepest thanks
and gratitude to Prof. Dr. Mohammad Yasser Metwally
for all of his guidance and support in this work. I'll
never forget his generous advice and kind supervision.
I would like to express also, my deepest thanks to
Dr. Amr
Abdel Moniem
for his
support, valuable
observations and friendly criticism.
Finally, I would like to thank my parents for their
great love and support.
Hesham El Adrousy
II
List of Figures
Figure
Title
Page
The p53 and retinoblastoma cell cycle and
12
NO.
1
cell death signaling pathways .
2
Sonic hedgehog signaling pathway.
20
3
Wingless signaling pathway.
21
4
Targeting growth factors & their
40
receptors, and downstream intracellular
effector molecules.
5
Therapies directed against cancer stem
41
cells.
6
Peptide-Based Vaccines.
54
7
Fusion of dendritic cells with tumor cells.
57
8
Recurrent glioblastoma treated with
66
bevacizumab and irinotecan.
9
Recurrent glioblastoma treated with
cediranib.
III
69
10
Gamma-Knife principle.
82
11
Photograph of the world’s first PerfeXion.
83
Gamma Knife.
12
The CyberKnife.
85
13
Mechanism of vector-mediated gene
132
therapy.
14
General mechanism of oncolytic virus
selectivity.
IV
138
List of Tables
Table
Title
Page
NO.
1
A comparison of Gamma Knife and
CyberKnife Radiosurgery
V
84
Introduction
&
Aim of the Work
Introduction & Aim of the Work
Introduction
Two large epidemiologic studies, one from the Mayo
Clinic and the second from the Central Brain Tumor
Registry of the United States (CBTRUS) gave a
remarkably similar incidence of symptomatic brain
tumors with a rate of about 12 per 100,000 populations
per year. Given the current United States population, this
comes to about 35,000 new patients with symptomatic
brain tumors who are diagnosed each year (De Angelis,
2005).
Brain tumors are the fourth most common solid
malignancy in the under 45 age group, and the eighth
most common in the under 65 age group. Overall, brain
tumors are the second most common cause of death from
neurological disease, after stroke (Hart and Grant,
2007).
Brain Metastasis is the most common intracranial
tumor, with an estimated annual incidence of more than
100,000 cases. In 20 to 40% of patients with cancer,
metastatic lesions travel to the brain (Sawaya et al.,
1994). Gliomas are the most common primary brain
tumors (Belda-Iniesta et al., 2006).
In children, brain tumors are the most common solid
tumor of childhood and are second only to leukemia in
their overall incidence of malignancies in the pediatric
population. In children, low grade astrocytomas and
medulloblastomas predominate. In adults, malignant
astrocytoma and meningioma are the most common
tumors (De Angelis, 2005).
Collected data on symptoms before and after surgical
resection report that 32% had an improvement in their
-1-
Introduction & Aim of the Work
symptoms, 58–76% were not different, and 9 –26% had a
worsening. Neurosurgery can improve some symptoms,
but it can also create new ones.
Neurological
complications
following
surgery
include
focal
haematoma,
abscess
and
seizures.
Systemic
complications include pneumonia and thromboembolic
disease. Morbidity rates range from 11% to 32%, with a
mortality rate of 0 –20% (Hart and Grant, 2007).
High-grade primary and metastatic brain tumors are
common, deadly, and refractory to conventional therapy
and have median survival duration of less than one year
(Heimberger and Priebe, 2008).
The diffuse infiltrative nature of gliomas makes
resection rarely complete and recurrence inevitable, so
resection is rarely curative (Hart and Grant, 2007).
Despite advances in radiation and chemotherapy
along with surgical resection, the prognosis of patients
with malignant glioma is poor. Therefore, the
development of a new treatment modality is extremely
important. Biotherapy for brain tumors will open a novel
reality now (Yamanaka and Itoh, 2007).
Medulloblastoma is the most common malignant brain
tumor of childhood. Surgery, radiation therapy, and
chemotherapy cure many patients, but survivors can
suffer long-term toxicities affecting their neurocognitive
and growth potential; furthermore, there is no curative
therapy in up to 30% of cases, m ainly because of our
incomplete understanding of many of the underlying
molecular and cellular processes (Grizzi et al., 2008).
There has been substantial progress in understanding
the molecular pathogenesis of these tumors, especially in
the critical role of tumor stem cells. In addition, there
have been important technologic advances in surgery and
-2-
Introduction & Aim of the Work
radiation therapy that have significantly improved the
safety of these therapies, and these advances have
allowed the widespread application of techniques, suc h
as stereotactic radiosurgery, to treat brain metastases
and some primary brain tumors that cannot be removed
surgically. Most excitingly, improved understanding of
the biology of brain tumors finally is being translated
into novel therapies using targeted molecular agents,
inhibitors of angiogenesis , and immunotherapies. The
preliminary results with these therapies are encouraging
(Wen and Schiff, 2007).
Immunotherapy is an appealing therapeutic modality
for brain tumors because of its potential to selec tively
target residual tumor cells that have invaded the normal
brain. Most immunotherapeutic studies are designed to
exploit the capacity of dendritic cells for inducing cell mediated effects as well as immune memory responses
for destroying residual tumor cells and preventing
recurrence (Parajuli et al., 2007). Recent reports
demonstrate
that
systemic
immunotherapy using
dendritic cells or peptide vaccines successfully induce an
antitumor immune response and prolong survival in those
patients without major side effects (Yamanaka, 2008).
Malignant tumors of the central nervous system are
difficult to cure, despite advances made in the fields of
neurosurgery and radiation oncology. These tumors are
generally resistant to standard chemotherapeutic agents,
and new strategies are needed to overcome these tumors.
Tumors of the brain demonstrate various features of
angiogenesis. Correlation has been made between the
degree of increased vascularity and outcome, making
these tumors enticing targets for anti-angiogenic agents.
Important advances in utilizing anti -angiogenic agents as
an additional therapeutic modality for patients with
central nervous system tumors have been identified.
-3-
Introduction & Aim of the Work
Rapid developments in understanding the molecular basis
of angiogenesis and brain tumors have been made over
the past decade, and application of this knowledge is
currently being brought to the clinic (Warren and Fine,
2008).
Overactivation of epidermal growth factor receptor
signaling has been recognized as an important step in the
pathogenesis and progression of multiple forms of cancer
of epithelial origin. The important role of aberrant
epidermal growth factor receptor signaling in the
progression of malignant gliomas makes epidermal
growth factor receptor-targeted therapies of particular
interest in this form of cancer. The use of anti -epidermal
growth factor receptor therapies against malignant brain
tumors, although in its infancy, promises to yield
exciting results as these new drugs probably will enhance
the usefulness of existing therapies (Nathoo et al.,
2004).
Combined inhibition of vascular endothelial growth
factor and platelet derived growth factor signaling
resulted
in
enhanced
apoptosis,
reduced
cell
proliferation, and clonogenic survival as well as reduced
endothelial cell migration and tube formation compared
with single pathway inhibition. So, dual inhibition of
vascular endothelial growth factor and platelet derived
growth factor signaling significantly increased tumor
growth delay versus each monotherapy (Timke et al.,
2008).
Combination
of
radiotherapy
with
vascular
endothelial growth factor and platelet derived growth
factor anti-angiogenic agents has the potential to
improve the clinical outcome in cancer patients (Timke
et al., 2008). Recent studies incorporating cytotoxic
therapy plus anti-vascular endothelial growth factor
-4-
Introduction & Aim of the Work
agents among recurrent glioma patients have achieved
unprecedented improvements in radiographic response,
time to progression and survival (Reardon et al., 2008).
In prolactin secreting pituitary adenomas, dopamine
agonists are considered the first-line of treatment.
Dopamine agonists (bromocriptine and cabergoline)
effectively normalize prolactin levels in as many as 89%
of patients and decrease tumor volume by at least 50% in
more than two thirds of patients within the first several
months of therapy. Recent reports highlight impressive
advancements in the pharmacologic treatment of growth
hormone-secreting adenomas. Traditionally, the two
options for medical therapy for these tumors have b een
dopamine
agonists
and
somatostatin
analogues.
Dopamine agonists provide symptomatic relief in the
majority of patients but normalize insu lin like growth
factor I levels only in approximately 20% to 40% of
cases.
Somatostatin
analogues
( octreotide
and
lanreotide) can normalize insulin like growth factor I
levels in up to 60% of patients and have a more favorable
side-effect profile compared with dopamine agonists
agonists. The recently introduced growth hormone
receptor antagonist (pegvisomant) has normalized insulin
like growth factor I levels in 90% to 100% of patients
who have refractory disease (Jagannathan et al., 2007).
Somatostatin and its analogues have the potential to
be effective in a wider group of pituitary and other
tumors. More potent and broad er-spectrum somatostatins
are likely to play an increasing role in the treatment of
tumors (Hubina et al., 2006). Somatostatin and its
analogues have direct anti-proliferative effect and anti angiogenic effect (Grozinsky-Glasberg et al., 2008). A
frequent finding in meningiomas is expression of
progesterone receptors. So, anti-progesterone treatment
-5-
Introduction & Aim of the Work
can be considered in recurrent unresectable benign
meningiomas (Sioka and Kyritsis, 2009).
Until recently, the use of systemic chemotherapy was
restricted and ineffective, due to the fact that the blood
brain barrier inhibits the adequate therapeutic
concentrations of most chemotherapeutic agents into the
tumor and peritumoral area (Argyriou et al., 2009).
Objective benefit from the temozolomide treatment
(stabilization or remission) was observed in 49% of
patients
irrespective
of
histological
diagnosis.
Tolerability of treatment with temozolomide in patients
with high-grade gliomas is good (Ziobro et al., 2008).
Temozolomide
can
also
enhance
tumor
cell
radiosensitivity in vitro and in vivo and this effect
involves an inhibition of DNA repair (Kil et al., 2008).
Radiosurgery is a procedure in which spatially
accurate and highly conformal doses of radiation are
targeted at well-defined structures with an ablative
intent. It has been used increasingly as a primary or
adjuvant treatment for various brain diseases, including
primary brain tumors, secondary metastatic tumors, and
arterio-venous malformations. Radiosurgery is used to
treat much smaller volumes of tissue a nd has
traditionally used a high dose of precisely focused
radiation delivered in a single session (Oh et al., 2007).
Gamma Knife Radiosurgery provides safe and
effective alternative treatment that is less invasive and
has fewer side effects (Nesbitt, 2007). Gamma Knife
Radiosurgery for brain metastases from conventionally
radioresistant primary cancers provides better local
control of the brain disease and improve s survival time
(Sin et al., 2009). Gamma Knife Radiosurgery for brain
metastases without prophylactic whole brain radiation
therapy prevents neurological death and allows a patient
-6-
Introduction & Aim of the Work
to maintain good brain condition (Serizawa et al., 2008).
Gamma Knife Radiosurgery also provides excellent
control of pineal region brain tumors when it is used in
conjunction with surgery, conventional radiation therapy,
or both (Lekovic et al., 2007). Gamma Knife
Radiosurgery can control hemangioblastomas for as
many as 10 years (Tago et al., 2005).
One of the novel strategies for treatment of brain
tumors is gene therapy that includes the use of diverse
viral and non-viral vectors and different genes to treat
these tumors (Benítez et al., 2008).
The development of new approaches for the treatment
of these tumors has led to the emergence of oncolytic
virotherapy, with the use of conditionally replicating
viruses, as a potential new intervention. Herpes simplex
virus type 1 has emerged as the leading candidate
oncolytic virus (Markert et al., 2006). These oncolytic
viruses can specifically replicate and lyse in cancers,
without spreading to normal tissues (Cutter et al., 2008).
-7-
Introduction & Aim of the Work
Aim of the Work
The aim of this review is to highlight the modern
trends in non-surgical treatment of brain tumors for
better management and prognosis of those patients.
-8-
Chapter (1)
Molecular
Pathogenesis
Of
Brain Tumors
Chapter 1
Molecular Pathogenesis
Molecular Pathogenesis of Brain
Tumors
Primary brain tumors are a genetically and
phenotypically heterogenous group of neoplasms that
vary prognostically as a function of location , pathologic
features, and molecular genetics (Levin et al., 2001).
They are comprised of tumors that originate from within
the brain and from structures associated intimately with
brain as meninges and ependymal tissues. Understanding
of molecular and genetic changes causing tumorigenesis
is critical for development of new therapeutic strategies
for brain tumors (Sauvageot et al., 2007).
Gliomas:
Gliomas are the most common type of primary brain
tumor and are grouped into three major categories
astrocytomas,
oligodendrogliomas,
and
mixed
oligoastrocytomas based on their histologic similarity to
normal astrocytes or oligodendrocytes. Gliomas are
subgrouped by WHO into grades based on histologic
factors, such as nuclear atypia, mitotic activity, vascular
proliferation, and necrosis. Tumor grad e is predictive of
patient survival (Sauvageot et al., 2007).
Astrocytomas:
Astrocytomas account for more than 60% of all
primary brain tumors (Cavenee et al., 2000). They are
classified into four grades. Grade I pilocytic
astrocytomas are essentially benign. Grade II diffuse
astrocytomas are characterized by nuclear atypia. Grade
III anaplastic astrocytomas show high mitotic activity
-9-
Chapter 1
Molecular Pathogenesis
and nuclear atypia. Grade IV glioblastomas are highly
infiltrative, proliferative, and necrotic. Glioblastomas
are the most common form of gliomas, accounting for
more than half of all primary gliomas and representing
more than 75% of astrocytomas (CBTRUS, 2006).
Glioblastoma subtypes:
Malignant
transformation
results
from
the
accumulation of genetic abnormalities, including
chromosomal loss, mutations, and gene amplifications
and rearrangements. Two subtypes of glioblastomas are
identified that are indistinguishable clinically but that
have different genetic profiles. Primary glioblastomas
typically appear in older patients wh o have no previous
history of the disease, whereas secondary glioblastomas
usually manifest themselves in younger patients as lowgrade astrocytomas that transform within 5 to 10 years
into glioblastomas (Sauvageot et al., 2007).
Defects in the p53 Apoptotic and Cell Cycle
Pathway:
P53 is a tumor suppressor gene that plays a critic al
role in apoptosis and cell cycle arrest. Loss of functionmutations in the p53 protein are found in more than 65%
of low-grade astrocytomas, anaplastic astrocytomas, and
secondary glioblastomas, suggesting that this is an early
event in formation of these tumors. Unlike secondary
glioblastomas,
primary
glioblastomas
infrequently
display mutations in p53 (less than 10%), although this
pathway is deregulated at other levels (Sauvageot et al.,
2007). Approximately 75% of glioblastomas exhibit
functional inactivation of the p53 pathway, which results
in defects in apoptosis and increased cell cycle
progression (Fig. 1) (Ichimura et al., 2000).
- 10 -
Chapter 1
Molecular Pathogenesis
Defects in the Retinoblastoma Cell Cycle
Pathway:
Retinoblastoma is a critical gatekeeper of cell cycle
progression by its ability to restrict or allow a cell to
progress through the G1 phase of the cell cycle pathway.
Hypophosphorylation of retinoblastoma maintains the
cell in a quiescent state by preventing the transcription
of genes important in mitosis. Retinoblastoma can be
phosphorylated by cyclin-dependent kinases 4 and 6,
which are regulated negatively by cyclin-dependent
kinase inhibitors, including p16Ink4a and p21Cip1. The
transition from low-grade to high-grade astrocytoma is
associated with allelic losses on chromosomes 9p and
13q and with amplification of 12q, which are
chromosomal loci that house genes associated with the
retinoblastoma pathway (Fig. 1). More specifically,
approximately 25% of high-grade gliomas have
mutations in retinoblastoma and 15% exhibit gene
amplification of cyclin-dependent kinase 4, whereas
inactivation of the p16Ink4a cyclin-dependent kinase
inhibitor occurs in 50% to 70% of these tumors
(Sauvageot et al., 2007).
Olig2 is a transcriptional repressor that is involved in
lineage specification in the nervous system (Novitch et
al., 2001). It is expressed in astrocytomas regardless of
grade, suggesting it is an early oncogenic event (Ligon et
al., 2004).
An article has revealed that Olig2 is required for
glioma formation and that it is a direct repressor of the
cyclin-dependent kinase inhibitor gene, p21Cip1 (Ligon
et al., 2007).
- 11 -
Chapter 1
Molecular Pathogenesis
Defects in Growth Factor Signaling:
Excessive signaling resulting from the overexpression
of either the growth factor ligand or the receptor gives a
proliferative and survival advantage to the cells leading
to their transformation and progression. The most
common defects in growth factor signaling involve the
platelet-derived growth factor and epidermal growth
factor signaling pathways (Sauvageot et al., 2007).
Fig . 1 . T he p 5 3 and r etino b lasto ma cell cycle and cell d eath signaling
p athways :
d o ub le
ar r o ws
ind icate
multistep
stimulatio n.
Rb :
r etino b lasto ma. p 1 4 ARF: p 1 4 alter nate read ing fro m, MDM2 : murine double
minute–2, B ax: B CL2 -asso ciated X p r o tein, cd c2 : cell d ivisio n cycle 2
( Sa uva g eo t et a l., 2 0 0 7 ) .
Overexpression of both platelet-derived growth factor
receptors and ligands within the same cells lead to
- 12 -
Chapter 1
Molecular Pathogenesis
autocrine loops, which can drive cell proliferation
(Sauvageot et al., 2007). Platelet-derived growth factor
activation promotes the upregulation of vascular
endothelial growth factor, which enhances angiogenesis
(Guo et al., 2003). Platelet-derived growth factor ligands
and receptors are found in low-grade and high-grade
astrocytomas, suggesting that this is an early oncogenic
event in secondary glioblastomas. Platelet-derived
growth factor receptors gene amplification is associated
with loss of function of p53, placing these two genetic
lesions as hallmarks of secondary glioblastomas
(Sauvageot et al., 2007).
Defects in epidermal growth factor receptors occur
almost exclusively in primary glioblastomas, where
approximately 40% of these tumors show amplification
of the region in chromosome 7 that encodes the
epidermal growth factor receptor gene (Sauvageot et al.,
2007). Overactivity of this receptor results in cellular
proliferation, tumor invasiveness, increased angiogenesis
and motility, and inhibition of apoptosis (Shinojima et
al., 2003). Within tumors exhibiting epidermal growth
factor receptors amplification, 40% also express a
constitutively autophosphorylated
variant
of
the
epidermal growth factor receptors that lacks the
extracellular ligand-binding domain, known as epidermal
growth factor receptor mutant version III . This truncated
receptor enhances tumorigenicity by increasing tumor
proliferation and invasiveness and decreasing apoptosis
(Lal et al., 2002).
Phosphatase and tensin homolog deleted on
chromosome 10 is a tumor suppressor gene that is
mutated or deleted in gliomas. Inactivating mutations in
phosphatase and tensin homolog deleted on chromosome
10 results in increased survival, proliferation, and tumor
invasion. Approximately 30% to 40% of glioblastomas
- 13 -
Chapter 1
Molecular Pathogenesis
exhibit mutations within the phosphatase and tensin
homolog deleted on chromosome 10 , which occur almost
exclusively in primary glioblastomas (Sauvageot et al.,
2007).
Oligodendrogliomas:
Oligodendrogliomas are diffusely infiltrating tumor s
whose cells resemble immature oligodendrocytes. They
account for more than 4% of all primary brain tumors and
represent approximately 20% of all glial tumors
(DeAngelis, 2001). Oligodendrocytomas are classified
into two grades, grade II oligodendroglioma and grade
III anaplastic oligodendroglioma (Sauvageot et al.,
2007).
Genetic alterations:
The main genetic abnormalities associated with
oligodendrogliomas are loss of chromosomes 1p and 19q,
which occur in approximately 50% to 90% of grade II
and grade III tumors, suggesting that this is an early
oncogenic event in the formation of oligodendrogliomas
(Jenkins et al., 2006). In addition, Olig2 is expressed in
grade II and grade III tumors (Ligon et al., 2004). The
retinoblastoma cell cycle pathway is altered in 65% of
oligodendrogliomas at the level of cyclin-dependent
kinases 4 amplification, mutations in retinoblastoma, or
deletions of p16Ink4a (Watanabe et al., 2001). p53 gene
mutations are seen in approximately 10% to 20% of all
oligodendrogliomas (Sauvageot et al., 2007).
Finally,
similar
to
high-grade
astrocytomas,
approximately 9% of anaplastic oligodendrogliomas
exhibit mutations in phosphatase and tensin homolog
deleted on chromosome 10, and more than 20% exhibit
loss of the 10q locus which houses phosphatase and
- 14 -
Chapter 1
Molecular Pathogenesis
tensin homolog deleted on chromosome 10 (Sasaki et al.,
2001). Such mutations, combined with growth factor
abnormalities, would result i n increased proliferation of
cells (Sauvageot et al., 2007).
Defects in Growth Factor Signaling:
Oligodendrogliomas also exhib it abnormalities within
the epidermal growth factor receptors and platelet
derived growth factor receptors signal transduction
pathways. Unlike astrocytomas, which exhibit epidermal
growth factor receptors amplification and overexpression
only in high-grade tumors, overexpression of this protein
occurs in approximately 50% of low-grade and highgrade oligodendrogliomas. Coexpression of platelet
derived growth factor ligands and receptors occur in
almost all oligodendrogliomas (Sauvageot et al., 2007).
Abnormalities within epidermal growth factor receptors
and platelet derived growth factor receptors signaling
indicate that this is an early oncogenic event in the
formation of these tumors (Weiss et al., 2003).
Oligoastrocytomas:
As their name implies, oligoa strocytomas are
composed of a heterogeneous population of cells that
have
characteristics
of
astrocytomas
and
oligodendrogliomas. Oligoastrocytomas are divided into
two grades, grade II oligoastrocytomas and grade III
anaplastic oligoastrocytomas which are clinically
aggressive and characterized by high mitotic activity,
nuclear atypia, and necrosis (Sauvageot et al., 2007).
The cellular heterogeneity seen in oligoastrocytomas
is reflected in the genetic heterogeneity of these tumors .
Approximately 30% to 50% of oligoastrocytomas exhibit
1p and 19q deletions reminiscent of oligodendrogliomas,
- 15 -
Chapter 1
Molecular Pathogenesis
whereas a separate 30% of these tumors house genetic
anomalies similar to astrocytomas, including mutations
in p53. Microdissection of the astrocytoma versus
oligodendroglioma components of these tumors have
revealed common genetic changes in all components of a
given tumor, suggesting that these histologically mixed
tumors may arise from a single transforming event
(Sauvageot et al., 2007).
Meningiomas:
Meningiomas originate from the transformation of
meningothelial cells and account for approximately 13%
to 26% of all primary brain tumors (Louis et al., 2000).
The large majorities of meningiomas are benign and
classified as WHO grade I tumors, although 5% to 7% of
all meningiomas are grade II atypical meningiomas, and
1% to 3% are grade III anaplastic meningiomas
(Sauvageot et al., 2007). Atypical meningiomas are
characterized by an increased mitotic index and sheeting
architecture, macronucleoli, hypercellularity, or necrosis,
whereas anaplastic meningiomas exhibit high mitotic
index and frank anaplasia (Perry et al., 2004).
Genetic alterations:
The most common change in meningiomas is loss of
heterozygosity of chromosome 22, which houses the
neurofibromatosis type 2 gene (Sauvageot et al., 2007).
Loss of function of neurofibromatosis type 2 is an early
event in approximately 60% of meningiomas and occurs
in almost all neurofibromatosis type 2 associated
meningiomas. The neurofibromatosis type 2 gene
encodes a protein known as merlin which is part of the
protein 4.1 family (Perry et al., 2004). Loss of merlin in
vivo is associated with increased cell growth and
formation of highly motile and metastatic tumors
- 16 -
Chapter 1
Molecular Pathogenesis
(Giovannini et al., 2000). Another protein 4.1 family
member known as DAL-1 has a growth suppressive
effect. It is lost in up to 76% of benign and atypical
meningiomas and 87% of malignant meningiomas
(Gutmann et al., 2000). Loss of protein 4.1R occurs in
40% of meningiomas (Robb et al., 2003). These data
suggest that the protein 4.1 family of proteins plays a
critical role in meningioma formation (Sauvageot et al.,
2007).
Telomerase enzyme is associated with tumor
progression, with infrequent expression in benign
meningiomas (approximately 8%) and higher levels in
atypical and anaplastic meningiomas (approximately 60%
and approximately 90%, respectively) (Falchetti et al.,
2002). Progesterone receptors are present in more than
80% of meningiomas. Progesterone receptors expression
is inversely proportional to tumor p roliferation and
histologic grade, with expression occurring in 96% of
benign tumors compared with 40% in malignant tumors.
Progesterone receptors expression is a favorable
prognostic factor for meningiomas (Sauvageot et al.,
2007).
Defects in Growth Factor Signaling:
Growth factors may play a role in meningioma
initiation and progression. Coexpression of Platelet
derived growth factor ligands and receptors occurs in the
majority of meningiomas (Sauvageot et al., 2007), with
higher expression correlating with increasing tumor
grade (Yang et al., 2001). Epidermal growth factor
receptors and their ligands; epidermal growth factor and
transforming growth factor α, are expressed in almost all
meningiomas but not in normal meninges. Increased
transforming growth factor α expression is associated
with aggressive meningioma growth. Insulin-like growth
- 17 -
Chapter 1
Molecular Pathogenesis
factor II, its receptor, and insulin-like growth factor
binding protein are expressed in meningiomas, where a
high ligand/receptor ratio is associated with malignant
progression (Sauvageot et al., 2007).
Medulloblastomas:
Medulloblastomas are an invasive embryonal tumor o f
the cerebellum that show tendency to metastasize.
Although medulloblastomas occur most frequently during
childhood, approximately 30% of cases arise in adults
(Sauvageot et al., 2007). Medulloblastomas are
considered WHO grade IV tumors because of their
invasive and malignant phenotypes and are grouped into
four subtypes consisting of: classic, desmoplastic,
extensive nodularity and large-cell medulloblastomas.
The histologic subtype is associated with the clinical
outcome (Eberhart et al., 2002).
Adult medulloblastomas differ from pediatric
medulloblastomas in terms of histology, locali zation, and
relapse frequencies (Carrie et al., 1994). Unlike
pediatric medulloblastomas, which are localized in the
midline cerebellar vermis and extend into the fourth
ventricle, approximately 50% of adult medulloblastomas
are located laterally within the cerebell ar hemispheres
(Prados et al., 1995).
Genetic alterations:
The
most
common
genetic
abnormality
in
medulloblastoma consists of an isochromosome of
chromosome 17, which arises in approximately 50% of
cases, and which occurs with a higher frequency in
classic than in desmoplastic medulloblastomas. Deletions
of the short arm of chromosome 17p also occur in 30% to
45% of cases. Although the tumor suppressor gene, p53,
- 18 -
Chapter 1
Molecular Pathogenesis
is located on 17p and is mutated in many cancer types,
only rare mutations in this gene are found in
medulloblastomas. Also deletions on chromosomes 1q
and 10q are found in 20% to 40% of medulloblastomas
(Sauvageot et al., 2007).
Defects in Growth factor Signaling:
The main growth factor pathways that are defective in
medulloblastomas are (Fuccillo et al., 2006):
1) Sonic hedgehog pathway.
2) ErbB pathway.
3) Wingless pathway.
Signaling within Sonic hedgehog pathway is initiated
by binding of the ligand Sonic hedgehog to its receptor
PTC that normally inhibits the activity of a protein
known as Smoothened. This binding removes inhibition
of Smoothened leading to release of glioma-associated
oncogene homolog-1 that enters the nucleus to activate
gene transcription (Fig. 2). Hence, PTC can play the role
of a tumor suppressor, whereas Sonic hedgehog and
Smoothened are putative oncogenes (McMahon et al.,
2003). Inactivating mutations of PTC was identified in
approximately
8%
of
medulloblastomas
whereas
activating mutations within Sonic hedgehog and
Smoothened was identified in rare cases (Sauvageot et
al., 2007).
ErbB2 is a receptor tyrosine kinase. Overexpression
of ErbB2 or a single point mutation in the
transmembrane domain of this receptor can induce tumor
formation (Yarden and Sliwkowski, 2001). 80% of
medulloblastomas show overexpression of ErbB2 which
is associated with a worse prognosis (Gajjar et al.,
- 19 -
Chapter 1
Molecular Pathogenesis
2004). The tendency of these tumors to metastisize may
be mediated in part by aberrant ErbB2 activation, as
ErbB2 overexpression in medulloblastomas increases cell
migration and promotes the upregulation of prometastatic
genes (Hernan et al., 2003).
Fig . 2 . So n ic hed g e ho g si g n al i n g p a t h wa y: S h h: So ni c hed g e ho g, SMO :
S mo o t h e ned , G LI 1 : gl io ma - a sso ci ated o nco ge n e ho mo lo g -1 , S u F:
s up p re s so r o f fu sed ( Sa uva g eo t e t a l ., 2 0 0 7 ).
Wingless activation of the frizzled t ransmembrane
receptor inhibits β-catenin degradation by the GSK3/APC/axin complex (Baeza et al., 2003). The resulting
increases in β-catenin levels enable it to enter the
nucleus and activate proliferation genes such as MYC
and cyclin D1 (Fig. 3) (Henderson and Fagotto, 2002).
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Chapter 1
Molecular Pathogenesis
Approximately 15% of sporadic medulloblastomas
exhibit mutations within Wingless pathway (Baeza et al.,
2003).
Fig . 3 . Win g less signaling p athway: W nt: W ingless , Dsh: d isheveled , LEF:
lymp ho id enhancer b ind in facto r , T CF: transcrip tio n facto r p ro tein, UUUU:
ub iq uitina tio n ( Sa uva g eo t et a l., 2 0 0 7 ).
Pathogenesis
Spread:
of
Brain
Tumors
In a mathematical model it has been calculated that
the velocity of expansion is linear with time and varies
from about 4 mm/year for low-grade gliomas and 3
mm/month for high grade gliomas (Swanson et al.,
2003). Motility and invasion of glioma cells are due to
events
involving
extracellular
matrix ,
adhesion
- 21 -
Chapter 1
Molecular Pathogenesis
molecules and properties
(Schiffer, 2006).
of
the
cells
themselves
Several genes involved in glioma invasiveness have
been identified and include members of the family of
metalloproteases. Expression of metalloprotease 2 and,
to a lesser extent, metalloprotease 9 correlates with
invasiveness, proliferation and prognosis in astrocytomas
(Wang et al. 2003).
Other non-metalloprotease proteases, including
urokinase-type plasminogen activator and cysteine
proteases (e.g. cathepsin B) , are elevated in high-grade
gliomas. Invasion inhibitory protein 45, a potential
tumor suppressor gene on chromosome 1p36, its product
inhibits invasion and it is frequently down-regulated in
glioblastomas. Other invasion- and migration-associated
genes have been identified including P311, deathassociated protein 3, and FN14 (Furnari et al., 2007).
Other proteins are overexpressed in invasive areas of
glioblastoma, such as angiopoietin-2, which in addition
to its involvement in angiogenesis also plays a role in
inducing
tumor
cell
infiltration
by
activating
metalloprotease 2 (Hu et al. 2003).
Many factors intervene in regulating cell migration
and invasion, first of all epidermal growth factor. Highly
amplified cells for epidermal growth factor receptors are
found at the invading edge of the tumor . Another very
important factor in regulation of glioma cell motility is
phosphatase and tensin homolog deleted on chromosome
10; its phosphatase-independent domains reduce the
invasive potential of glioma cells (Schiffer, 2006).
Phosphatase and tensin homolog deleted on chromosome
10 mutation has been implicated in an invasive
phenotype due to its ability to stabilize E-cadherin and
- 22 -
Chapter 1
Molecular Pathogenesis
modulate cell matrix adhesion complexes (Furnari et al.,
2007).
Integrins variously occur on glioma cells and mediate
cell adhesion to extracellular matrix (Tysnes and
Mahesparan,
2001).
Integrins,
especially
αVβ3
complexes, are elevated in glioblastomas and appear to
be relevant to processes of glioma invasion and
angiogenesis (Kanamori et al. 2004). Integrins also play
a role in glioma cell growth and proliferation. Other
factors involved in controlling cell motility are scatter
factor/hepatocyte growth factor and transforming growth
factor β1 (Schiffer, 2006).
Cell-of-Origin of Brain Tumors:
Primary malignant brain tumors have a high rate of
recurrence after treatment. Studie s have led to the
hypothesis that the root of the recurrence may b e brain
tumor stem cells, stem-like subpopulation of cells that
are responsible for propagating the tumor. Current
treatments combining surgery and chemoradiotherapy
could not eliminate brain tumor stem cells because these
cells are highly infiltrative and have several properties
that can reduce the damages caused by radiation or anti cancer drugs. Brain tumor stem cells are similar to the
neural stem cells. Furthermore, data from various models
of malignant brain tumors have provided evidence that
multipotent neural stem cells and neural progenitor cells
could be the cell origin of brain tumors. Thus, the first
event of brain tumorigenesis might be the occurrence of
oncogenic mutations in the neural stem cells or neural
progenitor cells. These mutations convert a neural stem
cell or neural progenitor cell to brain tumor stem cells,
which then initiates and sustains the growth of the tumor
(Xie, 2009).
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Chapter 1
Molecular Pathogenesis
What are Stem Cells?
Stem cells are defined as cells capable of self-renewal
and multipotency. Self-renewal refers to the ability of a
cell to generate an identical copy of it, whereas
multipotency refers to the ability to give rise to all the
differentiated cell types within a given tissue. Stem cells
are able to divide asymmetrically to produce mother and
daughter cells. The mother cell has equivalent selfrenewal and multipotency capabilities as the original
stem cell, whereas the daughter cell (a progenitor cell)
has a more limited set of developmental options and are
able to transiently divide before giving terminally
differentiated cells (Sauvageot et al., 2007).
Stem Cells in the Nervous System and in
Brain Tumors:
Historically, it has been believed that the cell -oforigin of gliomas must be a mature glial cell. More
recently, neural stem cells have been identified within
the adult brain, providing an alternate source of cycling
cells capable of transformation. Neural stem cells
capable of self-renewal and multipotency were identified
in germinal areas of the adult nervous system within the
subventricular zone and the dentate gyrus of the
hippocampus (Sanai et al., 2004).
Evidence suggests that tumorigenic stem cells also
exist within brain tumors. Initial reports showed that
neural stem cells could be isolated from glioblastomas
and medulloblastomas (Singh et al., 2003). Subsequent
experiments
revealed
that
xenotransplantion
of
neurospheres derived from human brain tumors could
form neoplasms that have the morphology and lineage
- 24 -
Chapter 1
Molecular Pathogenesis
characteristics of the original tumors (Singh et al.,
2004).
Implantation of as few as 100 of these cells that were
shown to express the stem cell surface marker, cluster
destination 133 (CD133), suffices to generate a tumor
compared with implantation of 10,000 cluster destination
133 negative cells, which are not able to form a tumor .
Several studies have indicated the presence of cluster
destination 133 positive brain tumor stem-like cells
within the human glioblastomas (Anhua et al., 2008).
These studies do not exclude the possibility t hat cycling
progenitor cells, or even more differentiated cells, also
may play a role in contributing the growth and
malignancy of these tumors (Sauvageot et al., 2007). The
neural progenitor cells are one source of gliomas as the
marker phenotypes, morphologies, and migratory
properties of cells in gliomas strongly resemble neural
progenitor cells in many ways (Canoll and Goldman,
2008).
Mouse Models:
Mouse models of gliomas, in which different
transforming
events
are
targeted
to
specific
subpopulations of cells within the nervous system, have
been created to help clarify the cell -of-origin of gliomas.
Although these experiments have shown that tumors can
arise from progenitor cells and from more differentiated
cells, they reveal that progenitor cells are more
permissive to oncogenic transformation (Holland et al.,
2000). This idea is supported by data showing that the
transforming epidermal growth factor receptors mutant
version III gene induces glial tumors more readily when
introduced into progenitor cells than in differentiated
ones (Bachoo et al., 2002).
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Chapter 1
Molecular Pathogenesis
These data reveal that malignant transformation
occurs more readily in progenitor cells, but that multiple
oncogenic pressures can drive more differentiated cells
to reacquire progenitor cell phenotype s, which
subsequently also can drive tumorigenesis (Sauvageot et
al., 2007).
Functional Similarities between Stem Cells
and Tumor Cells:
Several similarities exist between stem cells and
tumor cells, including 1) extensive proliferation, 2)
heterogeneity of progeny, and 3) high motility
(Sauvageot et al., 2007).
Neural stem cells and gliomas are highly
proliferative, and the epidermal growth factor receptors
are involved in this response in both cell types. It plays a
prominent role in promoting proliferation of gliomas,
both as a result of epidermal growth factor receptors
amplification, as well as expression of the constitutively
active epidermal growth factor receptor mutant version
III (Sauvageot et al., 2007).
Neural stem cells and gliomas show a diversity of
progeny. Neural stem cells can give rise to
heterogeneous population of cells. Likewise, gliomas are
a heterogeneous population of cells that arise from a
much localized transformation event, most likely
occurring in a multipotent tumor stem cell. In cases
where clonality cannot be established, this may suggest
that independent transformation events in different cells
of origin. Recent evidence reveals that some of the
heterogeneity may arise from progenitors that are
recruited to the tumor mass after the original
transformation event occurred (Assanah et al., 2006).
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Chapter 1
Molecular Pathogenesis
A cardinal feature of malignant gliomas is their
ability to migrate and infiltrate into adjacent regions.
Similarly, neural stem cells and neural progenitors
exhibit a migratory capacity in the normal adult brain
(Lois and Alvarez-Buylla, 1994). After injury, the
progenitor cells migrate from the subventricular zone to
the site of injury (Hayashi et al., 2005). Once again, this
shared phenotype may result from epidermal growth
factor activity and epidermal growth factor receptor
mutant version III which upregulates factors of tumor
invasion (Lal et al., 2002).
Molecular Similarities between Stem Cells
and Tumor Cells:
Several proteins that are normally involved in neural
stem cells development also are present in gliomas,
including platelet derived growth factor, phosphatase and
tensin homolog deleted on chromosome 10 , Oolig2, and
Sonic hedgehog, providing further support for the notion
that the origin of gliomas may be neural stem cells and
their progenitors (Sauvageot et al., 2007).
Coexpression of platelet derived growth factor
ligands and receptors are a common occurrence in brain
tumors. Platelet derived growth factor also plays an
important role in regulating glial progenitor proliferation
(Sauvageot et al., 2007). In the adult brain, platelet
derived growth factor receptor expression is restricted to
the germinal zone of the brain and, more specifically, is
expressed in a subset of subventricular neural stem cells
capable
of
differentiating
into
neurons
and
oligodendrocytes. Infusion of platelet derived growth
factor into the lateral ventricles induces the formation of
atypical hyperplastic cells that resemble gliomas
(Jackson et al., 2006).
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Chapter 1
Molecular Pathogenesis
Phosphatase and tensin homolog deleted on
chromosome 10 also is involved in the growth of neural
stem cells and gliomas. It is inactivated in a high
percentage of brain tumors, and this inactivation results
in increased cell migration, invasion, survival, and
proliferation. Correspondingly, phosphatase and tensin
homolog deleted on chromosome 10 plays a critical role
in neural stem cells maintenance and function (Li et al.,
2002).
Expression of Olig2 further extends the connection
between normal neural stem cells and gliomas. Olig2
expression found in all malignant gliomas is required for
glioma formation (ligon et al., 2007). During normal
development, Olig2 is expressed in precursor cells within
germinal areas of the brain (Menn et al., 2006), and is
necessary for normal and tumorigenic progenito r cell
growth (ligon et al., 2007).
Finally, the Sonic hedgehog and glioma-associated
oncogene homolog-1 signaling pathway controls the
proliferation of precursor cells within the adult germinal
zones (Sauvageot et al., 2007). A variety of primary
brain tumors express glioma-associated oncogene
homolog-1, and inhibition of this pathway inhibits tumor
growth (Dahmane et al., 2001).
In addition, targeted disruption of the Sonic hedgehog
receptor results in medulloblastoma formation . The
parallels between these developmental programs and
tumorigenesis lend further evidence that tumor formation
results from aberrations of developmental programs
normally active in normal neural stem cells and their
progenitors (Sauvageot et al., 2007).
- 28 -
Chapter 1
Molecular Pathogenesis
Localization of Stem Cell–Derived Tumors:
If normal neural stem cells are the cell of origin of
brain tumors, then it is expected that these neoplasms be
localized preferentially in the germinal areas of the
brain. Although this is not the case, much evidence
suggests that they arise from these areas and then
migrate out to their final locations (Zhu et al., 2005).
This dissociation of transformed cells from germinal
areas is consistent with current understanding of stem
cell niches (Li and Neaves, 2006). The germinal areas in
which stem cells reside are known as niches, and they
maintain a homeostatic balance of factors that control the
self-renewal and differentiation states of normal neural
stem cells revealing these cells’ dependence on the niche
for survival (Xie and Spradling, 2000). Tumorigenesis of
normal neural stem cells reflect mutations that make the
normal neural stem cells independent of the signals
necessary for self-renewal and survival in the niche,
thereby enabling it to grow at any location within the
brain. The ability of niche-independent normal neural
stem cells to migrate and grow in aberrant locations of
the brain is suggestive of the highly infiltrative nature of
brain tumors (Sauvageot et al., 2007).
- 29 -
Chapter (2)
Targeting Critical
Points
Chapter 2
Targeting Critical Points
Targeting Critical Points in
Brain Tumors Pathogenesis
Knowledge of the relevant pathogenesis pathways
aids selection of targets and agents. It is probable that,
for any given molecular target, multiple pathways and
multiple cell types can be affected. Different effects may
reinforce or contradict each other (Wieduwilt and
Moasser, 2008).
Before choosing a molecular target or pathway, it is
necessary to select the cell, or cells, that will be the
primary focus, and how directly they will be tied to
tumor attack. Targeted therapy could be directed also at
cells that participate in the antitumor immune response.
Once a molecular target has been chosen, what agent
should be selected to attack it, a small molecule
inhibitor, an antibody, does one prefer to stimulate an
immune response against the target (Lampson, 2009).
Despite the molecular heterogeneity of brain tumors ,
there exist common signal transduction pathways that are
altered in many of these tumors. In malignancies,
mutation or over-expression can occur in growth factor
ligands and their receptors, as well as in intracellular
effector molecules. Overexpression or mutations causing
activation of these growth factors and their downstream
effector
molecules
result
in
uncontrolled
cell
proliferation, survival, and invas ion (Mercer et al.,
2009). Targeting of these signaling pathways provides
new molecularly targeted treatment options (Argyriou
and Kalofonos, 2009).
- 31 -
Chapter 2
Targeting Critical Points
Targeting the Growth Factors and their
Receptors:
Growth factors bind to their receptors extracellularly
and initiate an intracellular signal transduction cascade.
Recent research has discovered many different
monoclonal antibodies and small-molecule inhibitors that
specifically target these ligands and receptors (Mercer et
al., 2009).
Targeting the Epidermal Growth Factor
Receptors:
Epidermal Growth Factor Receptor Inhibitors:
Epidermal growth factor receptor is amplified in 40–
60% of glioblastomas, and approximately 30–50% of
these tumors also possess the epidermal growth factor
receptor mutant variant III, in which coding regions in
the extracellular ligand domain are absent (Pelloski et
al., 2007). Epidermal growth factor receptors play an
integral role in the malignant phenotype of brain tumors,
and it is a common hope among researchers that
functional inhibition of epidermal growth factor
receptor-mediated signaling will slow tumor growth
(Sarkaria et al., 2007).
Treatment options that target epidermal growth factor
receptors include erlotinib and gefitinib (Fig. 4).
However, efficacy of these agents is modest (Argyriou
and Kalofonos, 2009). Erlotinib was evaluated in a
randomized phase II trial used in patients with recurrent
glioblastoma multiforme. The 6-month progression-free
survival was 12% (Mercer et al., 2009). Gefitinib was
evaluated in a phase II clinical trial in patients with the
first recurrence of a glioblastoma. The study showed a
- 32 -
Chapter 2
Targeting Critical Points
PFS-6 of 13% but no radiographic response was observed
(Argyriou and Kalofonos, 2009). Overall survival rates
in several phase I/II clinical trials for erlotinib and
gefitinib treatment were similar, but erlotinib was more
effective than gefitinib treatment in terms of objective
radiographic responses (Argyriou and Kalofonos, 2009).
Epidermal Growth Factor Receptor Peptide
Vaccines:
As mentioned previously, epidermal growth factor
mutant variant III is an attractive target because it is not
expressed in normal tissues but is expressed in a wide
number of malignancies, including 31–50% of malignant
gliomas (Heimberger et al., 2005). Initial preclinical
studies targeting epidermal growth factor mutant variant
III in rodents were promising. A peptide vaccine
targeting epidermal growth factor mutant variant III was
successful in extending the survival rate in vaccinated
rats by 72%. The success of these preclinical studies led
to several human trials that also produced promising
results (Ciesielski et al., 2005).
In a phase I human trial, patients were treated with up
to four peptide vaccines. The vaccine was well tolerated
and the majority showed increased cellular and humo ral
responses. Clinical results were moderately favorable; 5
of 21 patients showed a partial radiographic response and
8 of 21 had stable disease. The median survival among
patients with glioblastoma was 622 days (Yajima et al.,
2005).
Phase I human trial involving epidermal growth factor
mutant variant III the keyhole limpet vaccine showed that
the vaccine was well tolerated and the clinical results
were also promising in patients with malignant glioma.
The vaccine was successful in stimulating cellular
- 33 -
Chapter 2
Targeting Critical Points
immunity. Among patients with grade III tumors, 2 of 3
patients had stable disease. Among patients with
glioblastoma, the mean time to disease progression was
46.9 weeks. For the phase II trial, preliminary results
have indicated that the vaccine is well tolerated and
studies have demonstrated humoral and cellular
immunity; the final results have not yet been reported
(Sampson et al., 2008).
Targeting the Vascular
Growth Factor Receptors:
Endothelial
Vascular proliferation is a hallmark of tumor survival
and growth. It was suggested that patients with highly
vascularized tumors would have a poorer prognosis than
patients with less neovascularization; however, this
supposition requires further validation (DeGroot and
Gilbert, 2007).
Glioma cells produce many d ifferent proangiogenic
factors, including vascular endothelial growth factor. For
these reasons, vascular endothelial growth factor ligands
and receptors have been targeted for treatment of
gliomas. Strategies for targeting this ligand and its
receptor include using: 1) vascular endothelial growth
factor antibodies, 2) vascular endothelial growth factor
receptor tyrosine kinase inhibitors , and 3) protein kinase
C inhibitors (Mercer et al., 2009).
Bevacizumab is, to date, the most promising vascular
endothelial
growth
factor
monoclonal
antibody.
Bevacizumab targets the vascular endothelial growth
factor ligand with the goal of interfering with ligand receptor signaling (Fig. 4). Although at first there was
hesitation about using bevacizumab for the treatment of
patients with brain tumors, because of its known history
- 34 -
Chapter 2
Targeting Critical Points
of intra-tumoral hemorrhage in patients with colorectal
carcinoma (Mercer et al., 2009).
A phase II trial evaluated bevacizumab in
combination with chemotherapy (irinotecan). The
radiographic response rate was positive and 14 of 23
patients (61%) responded to therapy. The 6-month
progression-free survival was 30% and the overall
median survival time was 40 weeks (Vredenburgh et al.,
2007).
It was suggested that bevacizumab as monotherapy
may be the best way to maximize the efficacy of
treatment while minimizing systemic toxicity. In a phase
II trial of bevacizumab alone, the results showed that
approximately 60% of patients who were treated with
bevacizumab alone had objective radiographic responses ,
as well as a 6-month progression-free survival of 30%
and a median progression-free survival of about 110 days
(Fine, 2007).
Targeting the Platelet-Derived Growth
Factor Receptors:
Platelet derived growth factor and its receptors play
an important role in tumor interstitial pressure, tumor
growth, and angiogenesis. Over-expression of platelet
derived growth factor and its receptors in gliomas made
them to be targets for anti-tumor treatments (Ostman,
2004).
The platelet derived growth factor receptor inhibitor
for which most data have been obtained is imatinib
mesylate. Imatinib is a small-molecule inhibitor of
platelet derived growth factor receptors α and β (Fig. 4).
However imatinib showed some anti -tumor effects in
preclinical studies, minimal clinical benefit was seen
- 35 -
Chapter 2
Targeting Critical Points
using imatinib as monotherapy, with a radiographic
response rate of <6% and a 6-month progression-free
survival of <16% (Wen, 2006).
Imatinib with chemotherapy (hydroxyurea) showed
promising results (Dresemann, 2005). These initial
results of imatinib with hydroxyurea were supported in a
phase II trial in patients with recurrent glioblastoma,
which reported a radiologic response rate of 42% and a
6-month progression-free survival of 27% (Reardon et
al., 2005). The mechanism of action of this combination
is still unknown, but it has been shown that imatinib
decreases the interstitial tumor pressure and may
increase delivery of the chemotherapeutic agent
hydroxyurea. This gives a possible explanation for the
initial success associated with this combination.
Unfortunately, a phase III trial did not provide further
evidence of efficacy (Mercer et al., 2009).
There are many other therapeutic agents that are
beginning to be explored further such as sunitinib which
inhibits platelet derived growth factor receptors and
vascular endothelial growth factor receptors . Sunitinib
was shown in vivo to increase survival by 36% in mice
with glioblastoma. Also, treatment with sunitinib
increased tumor necrosis, reduced angiogenesis and
caused a 74% reduction in microvessel density
(DeBouard et al., 2007).
Another example is epidermal growth factor receptor
and vascular endothelial growth factor recepto r inhibitor
vandetanib that have been shown in vitro to have antitumor effects (Sandstrom et al., 2008).
- 36 -
Chapter 2
Targeting Critical Points
Targeting Downstream
Effector Molecules:
Intracellular
Activation of the growth factor receptors leads to
recruitment
of
intracellular
effector
mole cules
(downstream molecules) to the cell membrane. Gliomas
are associated with either the activation of these effector
molecules or the inactivation of their su ppressive
regulators. This stimulates cell proliferation and
invasion. Crucial pathways in gliomas are (Mercer et al.,
2009):
1) Ras/ Raf/MAPK,
2) PI3K/AKT/mTOR, and
3) Protein kinase C.
Ras/Raf/MAPK Pathway:
The Ras superfamily of genes regulates many
important cellular functions including cell proliferation,
differentiation, protein trafficking, and cytoskeletal
organization. The Ras pathway is an import ant
downstream of the epidermal growth factor receptors and
platelet derived growth factor receptors . Many
glioblastomas have hyperactive Ras pathway due to
mutation or amplification of their upst ream growth factor
receptors (Knobbe et al., 2004). Activation of Ras is
followed by overactivation of downstream Ras and Raf
molecules, which triggers Mitogen-Activated Protein
Kinase (MAPK), causing cell proliferation and release of
proangiogenic growth factors (Fig. 4) (Mercer et al.,
2009).
Tipifarnib and lonafarnib are the two most prominent
drugs used in an attempt to indirectly inhibit Ras . A
- 37 -
Chapter 2
Targeting Critical Points
phase II study of tipifarnib reported a 6-month
progression-free survival of 12% in patients with
glioblastoma and 9% in patients with anaplastic glioma
(Cloughesy et al., 2006). A phase I study of lonafarnib
with the chemotherapeutic agent, temozolomide, was
performed in patients with recurrent glioblastoma in an
attempt to overcome tumor resistance to temozolomide.
Using this therapy, 27% of patients who were previously
resistant to temozolomide treatment showed a partial
response, and the 6-month progression-free survival was
33% (Mercer et al., 2009).
PI3K/AKT/mTOR Pathway:
PI3K
(Phosphatidylinositol
3 -Kinase)
is
a
serine/threonine kinase that controls several malignant
characteristics as avoidance of apoptosis, and cell growth
and proliferation. Overactivation of Phosphatidylinositol
3-Kinase is a result of activation of receptor tyrosine
kinases such as epidermal growth factor receptors. This
pathway is down-regulated by phosphatase and tensin
homolog deleted on chromosome 10 . When phosphatase
and tensin homolog deleted on chromosome 10 function
is lost, activation of the Phosphatidylinositol 3 -Kinase
pathway occurs. Activation of this pathway activates
many downstream molecules including AKT (Fig. 4)
(Chakravarti et al., 2004).
AKT is also a serine/threonine kinase that decreases
apoptosis and therefore increases cell growth and
proliferation. AKT regulates many central biological
processes; therefore it is difficult to target it directly, so
inhibition of its upstream (preceding steps as
Phosphatidylinositol
3-Kinase)
and
downstream
(following steps as mammalian target of rapamycin ) has
been suggested (Fig. 4) (Mercer et al., 2009).
- 38 -
Chapter 2
Targeting Critical Points
mTOR (mammalian target of rapamycin) is a
downstream target of AKT (Vivanco and Sawyers, 2002).
Mammalian target of rapamycin controls important
cellular functions, including modulation of cell growth
(Fig. 4). Mammalian target of rapamycin inhibitors that
have been used in clinical trials are synthetic analogs of
rapamycin (e.g. temsirolimus, everolimus and sirolimus).
Phase II trials of temsirolimus in patients with
glioblastoma have not shown much efficacy. Although a
radiographic improvement was seen in 36% of patients,
no real survival benefit was recorded (Galanis et al.,
2005).
Protein Kinase C Pathways:
Protein Kinase C is a family of 14 protein kinases
that regulate cell growth, proliferation, and angiogenesis
(Couldwell et al., 1991). Protein Kinase C is a
downstream of growth factor receptors such as epidermal
growth factor receptors and platelet derived growth
factor receptors (Fig. 4) (DaRocha et al., 2002).
Tamoxifen and enzastaurin are the two protein Kinase
C inhibitors, for which significant data have been
recorded (Hui et al., 2004). Tamoxifen in glioma
xenografts showed some anti-tumor activity, but in the
clinical practice it showed only moderate efficacy with
no improvement in the median survival time (Spence et
al., 2004).
Enzastaurin has shown promising efficacy in the
clinical practice, with a 29% radiographic response rate
in patients with recurrent high -grade gliomas (Fine et
al., 2005). Progress with enzastaurin was stopped when
the phase III trial was stopped prematurely because the
significant survival benefits were not seen (Mercer et
al., 2009).
- 39 -
Chapter 2
Targeting Critical Points
Upstream
Downstream
Fig . 4 . T argeting gr o wth facto r s & their recep to rs, and d o wnstream
intracellu lar effecto r mo lecule s:
EGFR:
ep id ermal
gro wth
facto r
r ecep to rs ,
P DGF R: p la telet d er ived gro wth facto r recep to rs, VEGFR:
vascular end o thelial gr o wth facto r r ecep to rs , MAP K : mito gen-activated
p r o tein k inase , P KC: P r o tein Kinase C , P I3 K: P ho sp hatid ylino sito l 3 Kinase , mT OR: mammalian tar get o f rap amycin ,
(Arg yrio u a nd
Ka lo fo no s, 2 0 0 9 ) .
Targeting Cancer Stem Cells:
The evidence strongly suggests that the cells -oforigin of brain tumors are cancer stem cells or
transformed progenitor cells that arise from these stem
cells. Traditional therapies for brain tumors have focused
on shrinking the bulk of the tumor. As cancer stem cells
represent only a tiny minority of the tumor bulk,
therapies that focus on tumor bulk regression may not
eliminate all of the tumor-initiating cells completely,
- 40 -
Chapter 2
Targeting Critical Points
thereby enabling regrowth and recurrence. Furthermore,
the nature of stem cells makes them more resistant to
current therapies. Hence, therapies targeting tumor stem
sells are important in preventing recurrence of these
tumors (Fig. 5) (Sauvageot et al., 2007).
Fig . 5 . T her ap ies d ir ected against t he cancer stem cells wo uld eliminate the
cells cap ab le o f r ep o p ulating the tumo r, resulting in a tumo r that canno t
gro w (Sa uva g eo t et a l., 2 0 0 7 ) .
Selective eradication of cancer stem cells may be
achieved by targeting the tumor microenvironment rather
than the cancer stem cells directly. Anticancer therapies
combining anti-angiogenic and cytotoxic effects reduce
the cancer stem cell fraction in glioma xenograft tumors
(Folkins et al., 2007).
Targeting Tumor Spread:
Integrins are cell surface receptors tha t play
important roles in tumor invasion . Integrins, especially
αVβ3 complexes, are elevated in
glioblastoma
(Kanamori et al. 2004). Cilengitide is a drug that targets
integrins (αVβ3) and demonstrated some efficacy against
malignant gliomas in a preclinic al study and in a phase I
clinical trial. Considering these preliminary results,
cilengitide appears to be a promis ing treatment. A larger
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Chapter 2
Targeting Critical Points
phase II trial of cilengitide is currently ongoing in
patients with newly diagnosed glioblastomas concurrent
with radiation therapy (Argyriou and Kalofonos, 2009).
Matrix metalloproteinases are implicated in tumor
growth, invasion, extravasation into distant sites, and
angiogenesis.
The
most
well
studied
matrix
metalloproteinases inhibitor to date is marimastat. In
vitro studies have shown cytostatic effects. Animal
models have shown efficacy in preventing growth and
vascularization. Marimastat in combination with
chemotherapy (temozolomide) showed a 6-month
progression-free survival of 39%, compared with 18 to
21% with temozolamide alone. Prinomastat is a
lipophilic matrix metalloproteinases inhibitor, which
crosses the blood-brain barrier, making it promising for
the treatment of glioma (Vogelbaum and Thomas, 2007).
Src kinase facilitates cellular invasion. Targeted
deletion of Src in mice reduced glioma cell invasion.
Dasatinib, an inhibitor of Src kinase, is under clinical
development
in
recurrent
glioblastoma
patients
(Sathornsumetee et al., 2007).
Miscellaneous:
Proteasome Inhibitors:
The ubiquitin-proteasome system is important in
regulating cell proliferation and apoptosis. Proteasome
inhibitors can induce cell-growth arrest and apoptosis.
Bortezomib is a proteasome inhibitor that can induce
cell-cycle arrest and apoptosis in glioma cells. A phase
I/II study of bortezomib in gliomas is ongoing
(Sathornsumetee et al., 2007).
Deacetylase Inhibitors:
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Chapter 2
Targeting Critical Points
Histone deacetylase inhibitors target gliomas by
modifying gene transcription to cause cell -cycle arrest
and induction of apoptosis. Vorinostat, one of the histone
deacetylase inhibitors, was used in the treatment of
glioma and showed potential benefit. Pretreatment with
vorinostat can make glioma cells more susceptible to
chemotherapy and radiation (Chinnaiyan et al., 2005).
In a phase II trial of vorinostat in patients with
recurrent glioblastoma, the drug was well tolerated and
anti-tumor efficacy was noted; 6-month progression-free
survival was 23% (Galanis et al., 2007). Other
deacetylase inhibitors (e.g. romidepsin, LBH589, and
valproic acid) are being developed clinically for
treatment of glioblastoma (Mercer et al., 2009).
Ligand-Toxin Conjugates:
Glioma cells commonly express cell surface receptors
at greater density than normal brain cells. The ligands
for these receptors can be engineered to deliver toxins or
radioisotopes
to
produce
tumor
cytotoxicity
(Sathornsumetee et al., 2007).
Examples of these ligands include interleukin-13,
epidermal growth factor, and antibodies against tenascin C (extracellular matrix glycoprotein expressed by glioma
cells). Several ligand-toxin conjugates was developed for
glioma therapy including cintredekin besudotox, which
consists of IL-13 ligand conjugated to a pseudomonas
exotoxin. Cintredekin besudotox targets interleukin-13
receptors that are over-expressed in gliomas (Argyriou
and Kalofonos, 2009).
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Chapter 2
Targeting Critical Points
Small
Molecular
inhibitors
of Signal
Transducer and Activator of Transcription:
Signal transducer and activator of transcription is a
key transcriptional factor that drives the fundamental
components of tumor malignancy in CNS. Signal
transducer and activator of transcription promote
tumorigenesis by enhancing proliferation, angiogenesis,
invasion, metastasis, and immunosuppression. A group of
potent, small molecule inhibitors of signal transducer
and activator of transcription display marked efficacy
with minimal toxicity agai nst brain tumors in murine
models. The mechanism of this in vivo effic acy of Signal
transducer and activator of transcription inhibitors is a
combination of direct tumor cytotoxicity and immune
cytotoxic clearance. Given their ability to achieve good
CNS penetration, these drugs will be taken forward into
clinical trials for patients with CNS malignancies
(Heimberger and Priebe, 2008).
Heat Shock Protein 90 Inhibitors:
Heat shock protein 90 assists in protein foldin g and
cell signaling (Richter and Buchner, 2001). Heat shock
protein 90 is involved in folding, stabilization,
activation, and assembly of a wide range of proteins,
thus playing a central role in many biological processes.
Especially, several oncoproteins act as heat shock
protein 90 client proteins and tumor cells require higher
heat shock protein 90 activity than normal cells to
maintain their malignancy. For this reason, heat shock
protein 90 has emerged as a promising target for anti cancer drug therapy (Hahn, 2009).
Targeting of heat shock protein 90 may act either as a
direct anti-tumor agent, or as an enhancer of efficacy of
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Chapter 2
Targeting Critical Points
chemotherapy and radiotherapy. Heat shock protein 90
inhibition preclinically using geldanamycin against
glioma cells showed anti-tumor effects, and 17-AAG, a
less toxic derivative of geldanamycin, was shown to
inhibit tumor growth in glioma xenografts in mice (Yang
et al., 2001). 17-AAG exhibits promising antitumor
activity in clinical studies, but is limited by poor
solubility and hepatotoxicity (Zhang et al., 2009).
Challenges Associated with Targeted
Therapies:
There
are
many
controversies
surrounding
molecularly targeted therapies. Drug delivery across the
blood-brain barrier is one of the vital problems, so the
dilemma now is what is the most efficient way to deliver
drugs to the brain (Sawyers, 2006)? Also, it is difficult
for the drugs to reach the intraparenchymal regions in
the brain beyond the resection cavity. This becomes a
burden with micrometastases and infiltrative satellites
that are commonly seen in glioma (Mercer et al., 2009).
Therefore,
researchers
developed
convectionenhanced delivery as a novel way to deliver drugs across
the blood-brain barrier as well as over a large volume of
tissue. With convection-enhanced delivery, a catheter(s)
is placed in a predetermined area of the brain using
imaging techniques and the drug is infused over a period
of hours to days. A constant pressure gradient created by
an infusion pump permits the drug to be delivered
homogeneously to circumscribed areas of brain tissue
without causing significant tissue damage. This method
has become especially relevant in brain tumors as it
bypasses the blood-brain barrier and reduces systemic
toxicities (Mercer et al., 2009).
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Chapter 2
Targeting Critical Points
Lastly, higher efficiency of targeted therapies wil l
require technological advances that will improve
response evaluations. The progress of technology will
allow investigators to see whether treatment has true
antitumor effects or not (Mercer et al., 2009).
The Future of Targeted Therapies:
Targeting of a single signaling pathway in cancer may
not be sufficient to combat tumor progression, and it has
been theorized that targeting multiple growth factors may
be beneficial (Reardon et al., 2006). Combination
treatment regimen induced greater tumor cell apoptosis
and cell cycle arrest, and reduced proliferation compared
with single-agent therapy (Goudar et al., 2005).
The effects of these agents as a combination were
greater than their effects as monotherapies. There will be
a continuing effort to develop novel combinations of
targeted therapies in the future using the estimated 214
possible drug combinations available at present. With
this many combinations, there is infinite potential in
targeted therapies that remain to be expl ored (Mercer et
al., 2009).
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Chapter (3)
Immunotherapy
Chapter 3
Immunotherapy
Immunotherapy
Immunotherapy gives the promise of targeting tumor
cells for destruction with an excellent specificity and
efficiency, while at the same time almost completely
sparing normal cells from harm. The sensitivity and
specificity of the immune system is refined to the point
at which the body is capable of recognizing foreign
pathogens within minutes of infection, responding with
innate, humoral, and cellular effector mechanisms that
can control a rapidly expansive infection, and
eliminating almost all infected cell from the body. For
more than 100 years, tumor immunologists have hoped to
use this amazing cytotoxic power for use against
malignant cancer cells (Mitchell et al., 2008).
Immunologic Treatments for Brain Tumors
can take the form of (Mitchell et al., 2008) :

Passive immunotherapy: involving administration of
antibodies or toxins to the patients without
specifically inducing antitumor immune response in
vivo (inside the patients).

Active immunotherapy: involving immunization of
the patients to induce specific antitumor immune
response in vivo.

Adoptive immunotherapy: involving expansion of
effector cells (sensitized immune cells) ex vivo
(outside the patients) and introducing of these
effector cells to the patients (not commonly used
nowadays).
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Chapter 3
Immunotherapy
Passive Immunotherapy:
Passive immunotherapy may be defined as the transfer
of immunity to a patient in the form of either antibodies
(not developed by the patient) or targeted toxins
(Stragliotto et al., 1996).
Potential tumor antigens fall into two categories
consisting of ‘tumor-specific’ antigens, which are
composed of antigens that are only found within the
tumor and ‘tumor-associated’ antigens, which are
expressed in other tissues but overexpressed within the
tumor (Mercer et al., 2009).
Antibodies against tumor-specific antigens or tumorassociated antigens have been used as: [1] biologic
response modifiers (Bigner et al., 1998) and [2] delivery
system for other agents such as (a) radionucleotides, (b)
plant or bacterial toxins, or (c) chemotherapeutic agents
(Sampson et al., 2000).
Monoclonal Antibodies as Biologic Response
Modifiers:
Studies targeting epidermal growth factor receptor in
brain tumors have generally met with disappoin tment,
but a still promising use of antibodies as response
modifiers involves targeting epidermal growth factor
receptor mutant variant III (Sauter et al., 1996). In
preclinical studies, targeting of this mutant variant with
a single intratumoral injection of Y10 (anti-epidermal
growth factor receptor mutant variant III monoclonal
antibodies) increased the median survival of mice
bearing epidermal growth factor receptor mutant variant
III expressing tumors by an average of 286% (Sampson
et al., 2000).
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Chapter 3
Immunotherapy
The most exciting and promising advance in the use
of monoclonal antibodies as biologic response modifiers
has been the use of monoclonal antibodies against
vascular endothelial growth factor. Bevacizumab
(Avastins®) is anti-vascular endothelial growth factor
monoclonal antibodies. Recent studies examining the
capacity to inhibit the growth of tumors by combination
of bevacizumab and chemotherapy have shown promising
response rates and evidence of prolongation of survival
in recurrent glioblastoma (Vredenburgh et al., 2007).
Monoclonal Antibodies
Radionucleotides:
for
Delivery
of
The specificity of an antibody for a tumor antigen
allows its use as a delivery system for a variety of
effectors that may be conjugated artificially to the
antibody. These effector molecules are guided
specifically to their tumor targets by the antibody
specificity. Radionucleotides have been the most
commonly utilized conjugate (Brady, 1998).
The radiolabeled antibody 81C6 was used in a number
of clinical studies. Immunoreactivity and tumorlocalizing capacity of 81C6 have been reported as
superior to other anti-glioma monoclonal antibodies. It
has demonstrated both safety and ability to increase
survival in patients with leptomeningeal neoplasms ,
recurrent glioma, and newly diagnosed glioma. This
latter application, in particular, has demonstrated
promising results (Mitchell et al., 2008).
In 33 patients with newly diagnosed malignant glioma
treated with 81C6 monoclonal antibodies into the
surgically created resection cavity, there was a median
survival of 86.7 weeks for all patients and 79.4 weeks for
glioblastoma patients. These results were favorable in
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Chapter 3
Immunotherapy
comparison with prognostic factor -matched historical
controls and acceptable toxicity profile was observed
during this trial. A phase III study of the clinical
efficacy of 81C6 monoclonal antibodies treatment is
planned based on these encouraging data (Mitchell et al.,
2008).
Immunotoxins:
Plant and bacterial toxins represent alternative
biologic effectors that may be conjugated to eit her
antibodies or peptide ligands to produce either
immunotoxins or fusion toxins, respectively (Frankel et
al., 1995). These are designed to selectively deliver
toxins into tumors. Once arrived at their target, toxins
exhibit cytotoxicity. Such mechanisms give important
advantages for targeted toxins over radi otherapy or
chemotherapy (Hall and Fodstad, 1992). Therefore,
cancer cells exhibiting resistance to both radiotherapy
and chemotherapy may be susceptible to the cytotoxic
effects of a targeted toxin (Mitchell et al., 2008).
The truncated form of pseudomonas exotoxin has also
been used as a targeted toxin, which was conjugated to a
circularly interleukin-4 (Rand et al., 2000). The use of
interleukin-4 as the delivery system made benefit of a
proposed enrichment of interleukin-4 receptor on the
surface of glioma cells (Puri et al., 1994). The
interleukin-4 toxin conjugate is capable of arresting
tumor cell protein synthesis (Pastan et al., 1992). One
patient remained disease-free more than 18 months after
the procedure, and no systemic toxicities were observed.
Seven of nine patients treated required craniotomy
during protocol to relief increased intracranial pressure
(Rand et al., 2000).
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Chapter 3
Immunotherapy
A similar line of preclinical work has been translated
into clinical trials and includes targeting of the
interleukin-13 receptors that are known to be expressed
on a significant proportion of gliomas. A wide array of
human glioblastoma cell lines expressing the interleukin13 receptors were killed by a chimeric protein composed
of human interleukin-13 and a mutated form of
pseudomonas exotoxin (Debinski et al., 1995).
Recently published results of clinical trials using
intracerebral convection-enhanced delivery of this
chimeric protein showed capacity to induce tumor
necrosis but no clinical benefit in over 50 treated
patients with glioma (Kunwar et al., 2007). Recently
completed phase III study of treatment of first recurrence
of glioblastoma with convection-enhanced delivery of
this chimeric protein compared with chemotherapy by
carmustine wafers showed that the chimeric protein was
comparable but not statistically superior to carmustine
wafers (Mitchell et al., 2008).
Advantages and Disadvantages of Passive
Immunotherapy:
Results of passive immunotherapy trials have le ft
reason for optimism. Indeed, they offer much
improvement over current modalities in the field of
specificity. However, a number of limitations still exist
on the clinical efficacy of targeted treatment with
antibodies. The main unresolved problem stems from the
question whether treatments administered systemically
can achieve clinically significant levels at the site of
intracranial tumors. Sufficient levels may not be
achieved with the dosage and systemic route of
administration. It was demonstrated that 0.0006–0.0043%
of the total injected dose localized to the intracerebral
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Chapter 3
Immunotherapy
tumor following systemic intravenous administration;
thus, sufficient targeting of intracranial tumors may
require higher or more sustained doses of antibody in the
peripheral blood. Clinical attempts to ‘open up’ the
blood-brain barrier to drug delivery have met with both
failure and toxicity (Mitchell et al., 2008).
Other problems that remain for systemic delivery are
the high interstitial pressures in the tumor and
surrounding tissue which prevent perfusion. Furthermore,
systemic administration would require clearance by the
liver and/or kidney. This would be problematic during
delivery of conjugated radioisotopes or toxins, as it may
concentrate the toxic substances in these organ s (Jain,
1990).
As a result, antibodies are administered in almost
exclusively loco-regional fashion, providing them
specificity and enhanced targeting. Effectiveness of this
regional mode of delivery has been enhanced by the
emergence of convection-enhanced delivery (Choucair et
al., 1997).
Other challenges exist for the passive immunotherapy
of gliomas. Even with a tumor specific antigen , the
heterogeneity of these tumors makes it unlikely that
targeting a single antigen would produce a curative
therapeutic effect. In addition, the use of antibodies
introduces a problem that is the antibodies themselves
are antigenic. The development of human anti-human
antibodies against the therapeutic antibodies is not
infrequent event. This outcome may represent strict
limitations regarding repeated use of the therapy
(Mitchell et al., 2008).
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Chapter 3
Immunotherapy
Active Immunotherapy:
Active immunotherapy defines a strategy of initiation
of antitumor immune response in vivo following
immunization with tumor antigen (Yu et al., 2001).
The
ongoing
development
of
vaccine-based
immunotherapies offers a new hope for more effective
low-toxicity targeted treatments. A successful vaccine
for CNS cancers has been a ‘holy grail’ in neuro oncology. Recent clinical trials involving vaccines
against glioblastoma offer promising results. Other trials
have inspired additional hope and optimism in the field
of cancer immunotherapy (Ebben et al., 2009).
1. Peptide-Based Vaccines:
Peptide-based vaccines represent a major focus of
cancer vaccine research that offers exciting clinical
possibilities. The underlying assumption of peptide-based
cancer vaccines is similar to other conventional
vaccinations.
These
vaccines
are
produced
by
introducing small peptides that are immunogenic and
expressed by the targeted cancer cells (Fig. 6). These
peptides are processed by host antigen presenting cells,
which travel to the lymph nodes and sensitize cytotoxic
T-lymphocytes to the targeted cancer cells (Yamanaka
and Itoh, 2007).
The development of a peptide-based vaccine requires
successful isolation of an effective immunogenic peptide
that can be administered to induce an efficient in vivo
patient
immune
response
against
the
cancer.
Furthermore, this peptide must be universally expressed
by cancer cells, and must be in itself, crucial for tumor
survival. This could be particularly challenging, given
the heterogeneous nature of cancers, as well as the
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Chapter 3
Immunotherapy
difficulty in isolating and identifying a particular peptide
that demonstrates both specific restriction to cancer cells
and efficiently stimulates an appropriate antitumor
immune response (Ebben et al., 2009).
Inoculated
patient
Activated
CTLs
Peptide known to be
associated with CNS cancers
Stimulating
host immune
system
Fig . 6 . P ep tid e -B ased Vaccines . CT Ls: cyto to xic T -lymp ho cytes (Eb b en et
a l., 2 0 0 9 ) .
Targeting Epidermal
Growth
Receptors mutant variant III:
Factor
An epidermal growth factor receptors mutant variant
III-specific peptide has shown promise as an
immunogenic antigen. This peptide provides a novel
target for vaccine based therapies with a high degree of
specificity to glioblastoma tumor cells. In a phase I
clinical trial, glioblastoma patients were vaccinated with
the epidermal growth factor receptors mutant variant IIIpeptide after surgical resection. This approach resulted
in median time to progression of 46.9 weeks and overall
median survival of 110.8 weeks giving similar results to
current chemotherapy. The concern remains about the
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Chapter 3
Immunotherapy
universality of this approach to effectively treat
glioblastoma because not all glioblastomas express the
epidermal growth factor receptors mutant variant III
(Sampson et al., 2008). Although additional testing is
needed in other models, vaccination against epidermal
growth factor receptors mutant variant III could be of
therapeutic value (Ebben et al., 2009).
Wilms’ Tumor Peptide:
Other tumor-specific antigens have been identified as
Wilms’ tumor peptide produced by Wilms’ tumor gene.
This peptide was first identified in renal cancers as
Wilms’ tumor, but has been also isolated in a number of
haematopoietic and solid tumo rs. This gene is frequently
overexpressed in glioblastoma, and its protein product
has also demonstrated immunogenic properties, making it
an attractive target for potential vaccines (Ebben et al.,
2009).
A phase II clinical trial has been performed using the
Wilms’ tumor peptide for vaccination of patients with
recurrent glioblastoma. Twenty-one patients with failed
standard therapy were treated with intradermal injections
of Wilms’ tumor peptide weekly for at least 12 weeks.
Two patients showed partial response, ten patients had
stable disease and disease progressed in nine patients.
No adverse effects of vaccination were noted (Izumoto et
al., 2008).
Identifying Novel Antigens:
The continual refinement and development of new
tumor antigens is an essential component of the peptidebased vaccine development process be cause of the
inherent molecular heterogeneity of tumors that has been
one of the major challenges that hinder effective
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Chapter 3
Immunotherapy
implementation of peptide-based therapeutic strategies.
With the development of a more expansive library of
target antigens, there is ho pe that individualized, or
personalized, peptide-based vaccines can be developed.
The development of these vaccines would involve
exposing the immune system to multiple tumor antigens,
to evaluate their immunogenicity to identify a particular
immunogenic cocktail that will be most effective for the
given patient’s tumor (Itoh and Yamada, 2006).
In the case of pediatric glioma, three promising tumor
antigens were recently identified; ephrin receptor
EphA2, interleukin-13 receptor α2, and survivin (Okada
et al., 2008).
Another set of potentially fruitful targets is tumor
angiogenesis-associated antigens. In a phase I trial, six
patients with recurrent malignant brain tumors was
vaccinated with human umbilical vein endothelial cells.
MRI showed partial or complete resolution of enhancing
cancer masses in three patients. This may represent a
promising strategy. More research is needed to determine
whether this strategy promotes improved patient survival
(Okaji et al., 2008).
2. Dendritic Cell-Based Vaccines:
Another strategy used to induce an immune response
to CNS malignancy involves vaccination with patient
dendritic cells that have been treated with various tumor
components. Dendritic cells are specialized antigen
presenting cells. In their immature state, they show high
ability to capture and process antigens of all types. After
antigen capture, they mature and become excellent
antigen presenting cells (Banchereau and Steinman,
1998).
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Chapter 3
Immunotherapy
Several methods have been reported for stimulating or
charging dendritic cells with tumor antigens, including:
(1) pulsing of dendritic cells with tumor peptides , (2)
fusion of dendritic cells with tumor cells, and (3) loading
of dendritic cells with tumor lysate, apoptotic tumor
cells or tumor messenger RNA (Steinman and
Dhodapkar, 2001).
Fusion of dendritic cells with tumor cells (Fig. 7)
showed no adverse effects with this approach (Kikuchi et
al., 2001), and a second trial with co-administration of
interleukin 12 showed partial radiographic response in 3
of 12 patients (Kikuchi et al., 2004).
Inoculated
patient
Tumor
cells
Cell
fusion
Stimulating
host
immune
system
DCs
Activated
CTLs
Fig . 7 . Fusio n o f d end r itic cells with tumo r cells : DCs: d end ritic cells ,
CT Ls: cyto to xic T -lymp ho c y te s ( Eb b en et a l., 2 0 0 9 ) .
Loading of dendritic cells with
followed by vaccination of the patient
cells has also shown potential efficacy
overcoming chemotherapy resistance, a
- 57 -
tumor antigen
with the loaded
as a method of
serious problem
Chapter 3
Immunotherapy
that is frequently associated with higher grade gliomas
and glioblastoma (Liu et al., 2006).
3. Viral Vaccination Strategies:
In an effort to expand the library of target antigens, a
novel technique has been developed. Intratumoural
vaccination with herpes simplex virus has been
demonstrated to generate an immune response by
cytotoxic T-lymphocytes. After intratumoral injection of
herpes simplex virus into a mouse glioma model, a new
glioma-specific immunogenic antigen was identified and
isolated for study in future therapeutic strategies (Iizuka
et al., 2006).
Tumor was obtained from 23 patients and infected
with Newcastle disease virus. The tumor cells were then
irradiated and returned to the patient via subcutaneous
injection on a set schedule. Treated patients had a longer
time to progression and longer median survival than
those not receiving this therapy. Observation of resected
tumors from patients with recurrent disease revealed that
the vaccine induced an antitumour immune response
(Steiner et al., 2004).
4. Heat-Shock Protein Vaccination:
It is theorized that while each patient may have
unique tumor antigens, targeting of autologous heatshock proteins that are coupled with these unique tumor
antigens offers a method of targeting cancer cells
without the need to identify these unique tumor antigens
(Przepiorka and Srivastava, 1998). This technique
relieves clinicians from relying on a library of targets
that may not be complete or may not contain relevant
antigens (Amato, 2007). Studies of heat-shock protein
vaccination were found to effectively increase number of
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Chapter 3
Immunotherapy
active natural killer cells. This carries important
implications due to the vital role of natural killer cells in
the antitumor immune response (Qiao et al., 2008).
Current Vaccines:
There
are
several
promising
investigation in different phases:
agents
under
CDX-110 TM:
This is a peptide-based vaccine that targets epidermal
growth factor receptors mutant variant III. It is given
intradermally. The therapy was well tolerated and time to
progression from surgery was an impressive 12 months.
The median survival exceeded 18 months (Heimberger et
al., 2006).
DCVax TM:
This vaccine utilizes autologous dendritic cells
generated by leukopheresis (separation of white blood
cells) with antigenic peptides derived from patient’s own
tumor. In phase I study, treatment was well tolerated.
There were hematologic and local evidences of antitumor
response but no objective clinical response or survival
benefit were found (Liau et al., 2005). Currently, a
Phase II randomized trial targeting 141 patients with
newly diagnosed glioblastoma is ongoing (Das et al.,
2008).
Oncophage TM:
This vaccine is based on isolation of the heat-shock
proteins from the patient’s surgical specimen. This is
then delivered intradermally starting 2 –8 weeks after
surgery. This therapy was well tolerated and laboratory
studies found evidence of a tumor-specific immune
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Chapter 3
Immunotherapy
response that correlates with favorable clinical response
to therapy (Das et al., 2008).
Poly-ICLC:
This vaccine is a double-stranded ribonucleic acid
and stimulates the immune system broadly. In phase I
trial, therapy was well tolerated and 66% of patients had
an objective response and median survival for
glioblastoma patients was 19 months (Das et al., 2008).
Adoptive Immunotherapy:
Adoptive immunotherapy involves treatments that
include transfer of immune cells manipulated in some
fashion ex vivo (outside patients) to patients. Treatment
approaches have differed in the types of cells
administered, the route of administration, and the
activation status of the cells. Cell types that have been
used in adoptive immunotherapy include (Mitchell et al.,
2008):
(i)
Peripheral blood mononuclear cel ls.
(ii) Lymphokine-activated killer cells.
(iii) Mitogen-activated killer cells.
(iv) Tumor infiltrating lymphocytes.
(v)
Antigen-specific and unselected.
Routes of administration are generally either systemic
or into the tumor cavity. Infusing T-cell populations
previously activated against specific tumor antigens is
one strategy of adoptive T-cell therapy (Mitchell et al.,
2008).
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Chapter 3
Immunotherapy
Blood Vessels:
Immunotherapy
and
Brain
Tumor
A stimulating new approach to immunotherapy for
tumors involves the immunologic targeting of tumor
endothelial cells for destruction instead of the targeting
of the tumor itself. Tumor endothelial cells express
distinct antigenic markers that can be exploited in
vaccine strategies (Wei et al., 2002).
It is currently being investigated whether strategies
involving transfer of tumor endothelium-specific T cells
can effectively inhibit tumor growth through cutting off
of blood supply. There are several advantages to this
approach: (1) the potential for killing many tumor cells
per effector lymphocyte, (2) the ability to avoid escape
mutations, (3) the lack of concern of T-cell movement
across the blood-brain barrier because the endothelial
targets are in contact with the blood, and (4) such
approach may overcome the limitations of cytostatic
angiogenic therapy, in which escape mechanisms
frequently occur (Mitchell et al., 2008).
Immunotherapy and Brain Tumor Stem
Cells:
The brain tumor stem cells are widely believed to be
responsible for tumor propagation and re sistance to
conventional therapies. Some anti-tumor approaches may
spare brain tumor stem cells. Therapies targeting
molecular properties that define these cells have a
greater biologic impact and reduce the need for intensive
conventional therapy (Liu et al., 2006).
Although brain tumor stem cells appear resistant to
radiation and chemotherapy, their susceptibility to
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Chapter 3
Immunotherapy
immunotherapy has not been formally tested. A recent
study in a glioma model has shown that the immunologic
targeting of brain tumors using dendritic cells pulsed
with lysates from tumor cells grown in stem-cell culture
media was more efficacious than dendritic cells pulsed
with tumor lysates from cells grown in standard culture,
suggesting that targeting of brain tumor stem cells may
be of therapeutic benefit. Thus, identification of antigens
expressed in brain tumor stem cells and development of
immunotherapy that effectively targets these brain tumor
stem cells is a promising approach for treatment of brain
tumors (Mitchell et al., 2008).
New Hope in Immunotherapy:
The recent advances carry great promise for
development of immunotherapies that will lead t o
significant and reliable anti tumor responses. They also
hold significant promise for having a favorable impact
on patient survival. Although immunotherapy did not
emerge as a single-modality treatment for brain tumors,
it will take its place as a very effective adjuvant therapy
(Mitchell et al., 2008). Dendritic cells and peptide-based
therapies appear promising as an approach to
successfully induce antitumor immune response and
prolong survival. Dendritic cells and peptide-based
therapies seem to be safe and without major side effects.
Its efficacy should be determined in randomized and
controlled clinical trials (Yamanaka, 2009).
An effective vaccine will be a potent addition to the
current therapeutic approaches against brain tumors.
Significant progress has been made that offers new hope
and novel therapeutic opportunities. It is important to
realize that much additional work lies ahead b efore an
effective brain tumor vaccine is validated for clinical use
(Ebben
et
al.,
2009).
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Chapter (4)
Anti-angiogenic
Therapy
Chapter 4
Anti-angiogenic Therapy
Anti-angiogenic Therapy
Angiogenesis, the growth of new blood vessels from
pre-existing vessels, is considered to be the key
regulating factor of vascular development of brain
tumors and especially for glioblastoma multiforme. The
development and growth of malignant glioma seems to be
dependent on angiogenesis, since the microvascular
proliferation can only be observed in high grade gliomas.
Additionally, the aggressiveness and clinical recurrence
of malignant gliomas are closely related to the degree of
neovascularization (Argyriou et al., 2009).
The discovery that tumor pro gression depends on
angiogenesis led to the development of anti-angiogenic
therapy for cancer (Kerbel, 2008). A large body of
preclinical evidence suggests that anti -angiogenic
therapy may be effective in treating gliomas , and
preliminary clinical data suggest that anti -angiogenic
agents have a beneficial effect in patients with gliomas
(Norden et al., 2008).
Currently, anti-angiogenic molecularly targeted
therapies including administration of monoclonal
antibodies or tyrosine kinase inhibitors are being
increasingly adopted for treating glioblastoma (Argyriou
et al., 2009).
Furthermore, antiangiogenic agents have potent antiedema (Fig. 8 and 9) and steroid-sparing effects in
patients. Emerging data suggests that these drugs may
modestly improve progression-free survival (Chi et al.,
2009).
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Chapter 4
Anti-angiogenic Therapy
Vascular Endothelial Growth Factor
Pathway Inhibitors:
Because of vascular endothelial growth factor
prominent role in glioma angiogenesis, its pathway was
rapidly identified as an attractive therapeutic target.
Thus; agents that target the vascular endothelial growth
factor pathway have become the most clinically advanced
anti-angiogenic drugs. Vascular endothelial growth
factor-targeting approaches include strategies that target
vascular endothelial growth factor ligand and receptors
(Chi et al., 2009).
Vascular Endothelial Growth Factor Ligand
Inhibitors:
Bevacizumab (Avastin®) is a humanized monoclonal
antibodies against vascular endothelial growth factor
ligand. Aflibercept is a soluble vascular endothelial
growth factor decoy receptor (vascular endothelial
growth factor Trap). Both of them are vascular
endothelial growth factor sequestering molecules (hide
and isolate the factor) and characterized by high
specificity (Chi et al., 2009).
In the first reported prospective study of an anti vascular endothelial growth factor therapy in malignant
glioma, high radiographic response and 6-month
progression-free survival proportions were observed with
the combination of bevacizumab and conventional
chemotherapy (Vredenburgh et al., 2007).
In a phase II clinical trial, 68 pa tients (33 recurrent
anaplastic glioma and 35 recurrent glioblastoma) were
treated with bevacizumab and chemotherapy (irinotecan).
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Chapter 4
Anti-angiogenic Therapy
Radiographic response (Fig. 8) proportions of 57% for
recurrent glioblastoma and 61% for recurrent anaplastic
glioma patients were observed. Responses were also
associated with neurological improvement and reduction
or discontinuation of corticosteroid requirements .
Although treatment was generally well tolerated, toxicity
was observed. There were thromboembolic complications
in 8 of the 68 patients (12%), and 2 patients (3%) had
CNS hemorrhages (Wagner et al., 2008).
Additionally, several retrospective studies have
reported similar findings with bevacizumab in recurrent
malignant glioma. Radiographic response proportions
between 35% and 50% have been observed with the
combination
of
bevacizumab
and
conventional
chemotherapy in several case series with responses often
occurring rapidly after treatment initiation (Guiu et al.,
2008). These studies also reported delayed tumor
progression, suggesting that clinical benefits were
derived. One study reported that 6-month progressionfree survival was 42% for recurrent glioblastoma
patients, and apparent antiedema effect of bevacizumab
was evident, in that 33% of patients reduced their
corticosteroid requirements. Treatment was generally
well tolerated in these retrospectiv e series, although
thromboembolic and hemorrhagic complications were
reported (Norden et al., 2008).
All of these studies were of bevacizumab in
combination with cytotoxic chemotherapy. Bevacizumab
was most often combined with irinotecan in these
studies, and irinotecan is known to have minimal
efficacy in recurrent malignant glioma patients
(Batchelor et al., 2004). How much chemotherapy
contributed to the effect of bevacizumab and whether
bevacizumab
had
single-agent
activity
remained
unanswered. To address these questions, a phase II trial
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Chapter 4
Anti-angiogenic Therapy
randomized 167 recurrent glioblastoma patients to
receive either bevacizumab alone (10 mg/kg every 2
weeks) or in combination with irinotecan. The
radiographic response and 6-month progression-free
survival proportions were 37.8% and 50.3% respectively,
with combination therapy. These were similar to the
proportions seen with bevacizumab alone (28.2% and
42.6%, respectively). In addition, the median overall
survival for the combination therapy (8.7 months) was
similar to that observed with bevacizumab alone (9.2
months). In this study, most patients were able to reduce
their corticosteroid dose by at least 50%, and treatment
was well tolerated (Cloughesy et al., 2008).
Fig . 8 . A 4 4 -year -o ld man with r ecur r ent glio b lasto ma (A) treated with
b eva cizu ma b and irin o teca n : sho wing marked red uctio n in enhancement
after 4 weeks o f ther ap y ( B ) ( Ca va liere et a l., 2 0 0 7 ) .
Another recently reported phase II study evaluated
the benefit of bevacizumab monotherapy in recurrent
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Chapter 4
Anti-angiogenic Therapy
glioblastoma patients. In 48 patients, the authors
observed a 35% radiographic response and a 6-month
progression-free survival of 29%. Furthermore, when
irinotecan was added to bevacizumab at progression in
19 patients, there were no objective radiographic
responses. These two studies suggest that irinotecan adds
little, if any, benefit to bevacizumab (Kreisl et al.,
2009).
Aflibercept is a soluble vascular endothelial growth
factor decoy receptor that consists of a vascular
endothelial growth factor receptor fused to an
immunoglobulin constant region. It has vascular
endothelial growth factor receptors binding affinity
several hundred times greater than bevacizumab (Holash
et al., 2002). An ongoing phase II clinical trial of 48
recurrent malignant glioma patients treated with
aflibercept monotherapy reported response proportions
of 50% for anaplastic glioma and 30% for glioblastoma
patients, values similar to the response proporti ons
observed in bevacizumab trials. There was moderate
toxicity; however, treatment was discontinued in 12
patients (25%), on average less than 2 months into
therapy (De Groot et al., 2008).
Vascular
Endothelial
Receptor Inhibitors:
Growth
Factor
Currently many vascular endothelial growth factor
receptors-targeted tyrosine kinase inhibitors are in
clinical trials for malignant gliomas. These small
molecule inhibitors were initially developed as specific
inhibitors of the vascular endothelial growth factor
receptors, but they have the capacity to inhibit many
other receptors such as the platelet-derived growth factor
receptor. Although this lack of specificity may result in
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Chapter 4
Anti-angiogenic Therapy
more off-target effects, the potential for simultaneous
inhibition of several proangiogenic pathways may be a
favorable feature (Karaman et al., 2008).
Cediranib is potent pan-vascular endothelial growth
factor receptors tyrosine kinase inhibitors with modest
activity against platelet-derived growth factor receptors.
In a recent phase II trial of cediranib monotherapy in
recurrent glioblastoma patients, radiographic response
(Fig. 9) was observed in 56% of patients and the 6-month
progression-free survival was 26%. There was also a
modest improvement in median overall survival in
cediranib-treated patients relative to a historical
database. Furthermore, an anti-edema effect (Fig. 9) was
detected with cediranib monotherapy and corticosteroid
requirements were discontinued or decreased in 15 of 16
patients. Toxicity was moderate; only 2 of 31 patients
were removed from the study because of toxicity and no
treatment-related deaths or intracranial hemorrhages
occurred, a high frequency of hypertension was
observed. Fatigue and diarrhea were also frequent
toxicities (Batchelor et al., 2008).
As a result of this study, a phase II study of cediranib
with chemotherapy and radiation in newly diagnosed
glioblastoma has been launched, and a multicenter,
randomized phase III trial in recurrent glioblastoma is
underway, comparing cediranib versus cediranib plus
chemotherapy (Chi et al., 2009).
Vatalanib, an inhibitor of the vascular endothelial
growth factor receptors and platelet derived growth
factor receptors tyrosine kinases, has been clinically
investigated in several advanced solid tumors (Thomas et
al., 2005). Several phase I/II clinical trials have studied
vatalanib in recurrent glioblastoma patients, either as
monotherapy (Conrad et al., 2004) or in combination
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Chapter 4
Anti-angiogenic Therapy
with chemotherapy (Reardon et al., 2004). Clinical
benefits were limited in these studies. Response
proportions ranged between 4% and 8%, and progressionfree survival was not significantly higher than historical
benchmarks. These results may have been affected by
suboptimal dosing. More recently, the combination of
vatalanib, the platelet derived growth factor receptors
inhibitor imatinib, and chemotherapy resulted in a
modest response proportion (22%) in a phase I trial of 37
recurrent malignant glioma patients (Kirkpatrick et al.,
2008).
Fig . 9 . A 4 7 -year -o ld wo man with recurrent glio b las to ma treated with the
p an-vascular end o thelial gr o wth facto r recep to rs inhib ito r ( ced ira n ib ) :
sho wing mar ked r ed uctio n o f T 1 -co ntrast enhancement (up p er ro w) and
p eri-tumo r al ed ema o n FLAI R images (lo wer ro w) o ver 5 6 d ays (Ca va liere
et a l., 2 0 0 7 ) .
The broad-spectrum tyrosine kinase inhibitors
sorafenib and sunitinib have the capacity to inhibit a
number of tyrosine kinases including
vascular
endothelial growth factor receptors and platelet derived
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Chapter 4
Anti-angiogenic Therapy
growth factor receptors (Morabito et al., 2006). Both
agents are being studied in early phase clinical trials for
recurrent malignant glioma. Sorafenib is being evaluated
as monotherapy and in combinations with the mammalian
target of rapamycin inhibitor temsirolimus and epidermal
growth factor receptor inhibitor erlotinib. Sunitinib is
being studied as monotherapy and in combination with
chemotherapy (irinotecan). Mature data have yet to be
reported, although to date these agents appear to be only
moderately well tolerated. In addition, several other
vascular endothelial growth factor receptors inhibitors
are in clinical trials for recurrent malignant glioma as
single agents or in combination regimens (Chi et al.,
2009).
Non-Vascular
Endothelial
Factor Pathway Inhibitors:
Growth
Epidermal
Inhibitors:
Receptor
Growth
Factor
Cetuximab targets the extra cellular domain of the
epidermal growth factor receptors . The clinical relevance
of this effect is currently under investigation in patients
with recurrent glioblastoma (Sadones et al., 2006). A
phase I/II study investigating the efficacy and safety of
cetuximab plus concomitant chemoradiotherapy is
currently ongoing (Argyriou et al., 2009).
Treatment options which target epidermal growth
factor receptors mainly include the administration of
gefitinib and erlotinib. Gefitinib (500–1,000 mg orally)
has been tested in a phase II trial assessing 57 patients
with first recurrence of a glioblastoma. Gefitinib yielded
a modest degree of efficacy, while no neuroimaging
response was observed. The 6-month progression-free
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Chapter 4
Anti-angiogenic Therapy
survival was 13%, and the median overall survival time
was 39.4 weeks (Rich et al., 2004). Likewise, limited
activity was observed in another phase II trial of
gefitinib assessing patients with malignant glioma
recurrence following surgery plus radiotherapy and
chemotherapy. The 6-month progression-free survival
was 14.3% and the median overall survival was 24.6
weeks (Franceschi et al., 2007). Considering these data,
monotherapy with gefitinib is not superior in terms of
efficacy over conventional chemotherapy (Argyriou et
al., 2009).
Erlotinib seems to influence the survival rates of
patients with malignant glioma to a similar degree. In a
multicentre phase I trial, 19 patients with glioblastoma
were treated with erlotinib plus radiation therapy,
median overall survival was 55 weeks (Krishnan et al.,
2006). In another study, 83 patients with stable or
progressive malignant glioma received monotherapy with
erlotinib or in combination with chemotherapy
(temozolomide). Eight of 57 finally assessed patients had
a partial response and 6 had a progression-free survival
of longer than 6 months (Prados et al., 2006).
Overall, therapy with erlotinib or gefitinib is
associated with modest therapeutic efficacy in only few
patients with malignant gliomas. Therefore, biomarkers
reliably predicting the response of gliomas to these
agents need to be identified (Argyriou et al., 2009).
Platelet Derived Growth Factor Receptor
Inhibitors:
The platelet derived growth factor pathway plays an
important role in angiogenesis and thus represents a
particularly attractive therapeutic target (Jain et al.,
2007). Clinical trials evaluating the platelet derived
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Chapter 4
Anti-angiogenic Therapy
growth factor receptors inhibitor imatinib as a single
agent in recurrent malignant glioma patients have been
disappointing. The 6-month progression-free survival
rate was 16% for glioblastoma (Raymond et al., 2008).
Combination
of
imatinib
with
chemotherapy
(hydroxyurea) in several studies reported promising 6month progression-free survival proportions in recurrent
malignant glioma patients (24%–32%) (Desjardins et al.,
2007). However, a recent large multicenter study failed
to confirm these findings (Dresemann et al., 2008).
The newer platelet derived growth factor receptors
inhibitors, tandutinib and dasatanib, have potentially
greater efficacy in malignant glioma patients, due to
improved CNS penetration, and they are in clinical trials
for recurrent malignant glioma (Chi et al., 2009).
Fibroblast Growth Factor Inhibitors:
The fibroblast growth factor pathway is an important
proangiogenic pathway. Recently, the fibroblast growth
factor pathway has been implicated in resistance to
vascular endothelial growth factor receptors -targeted
therapy (Bergers and Hanahan, 2008). Strategies
targeting fibroblast growth factor had limited efficacy in
malignant glioma patients in earlier trials as the
inhibitors used in these studies were relatively
nonspecific (Chi et al., 2009).
Thalidomide, an inhibitor of both fibroblast growth
factor and vascular endothelial growth factor , was shown
to have minimal activity as monotherapy or in
combination
with
chemotherapy
(carmustine
or
temozolomide) (Baumann et al., 2004). The more potent
thalidomide analog lenalidomide has better tolerability;
however, there was little suggestion of efficacy, either as
a single agent or in combination with radio therapy. There
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Chapter 4
Anti-angiogenic Therapy
were no radiographic responses with lenalidomide
monotherapy in 24 recurrent glioblastoma patients (Fine
et al., 2007) and one response in 20 newly diagnosed
glioblastoma patients treated with lenalidomide in
combination with radiotherapy (Drappatz et al., 2009).
Toxicities associated with this class of agents, which
include overlapping hematologic toxicity between
lenalidomide and chemotherapy, may limit further
clinical development (Chi et al., 2009).
Several other inhibitors of the fibroblast growth
factor pathway had limited efficacy in clinical trials of
malignant glioma patients, including interferon-α,
interferon-β and suramin. Fibroblast growth factor
receptor tyrosine kinase inhibitors with greater
specificity for the fibroblast growth factor pathway were
developed. These drugs, which include tyrosine kinase
inhibitors 258, XL-999, brivanib and BIBF1120, have
potential utility in malignant glioma patients (Chi et al.,
2009).
Protein Kinase C Inhibitors:
Signaling through the protein kinase C pathway plays
an important role in angiogenesis. The protein kinase C
inhibitor, enzastaurin, was evaluated as monotherapy in
a phase III randomized trial, compared against
chemotherapy (lomustine), in recurrent glioblastoma, but
the study was stopped because efficacy milestones were
not met (Fine et al., 2008).
Cyclooxygenase-2 (COX-2) Inhibitor:
Cyclooxygenase-2, which promotes the expression of
proangiogenic factors (Iniguez et al., 2003) has been
targeted in recurrent malignant glioma patients with the
selective cyclooxygenase inhibitor celecoxib. However,
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Chapter 4
Anti-angiogenic Therapy
only modest 6-month progression-free survival of 19%
and 25% was observed when celecoxib was combined
with chemotherapy (irinotecan) (Reardon et al., 2005)
and 13-cis-retinoic acid, respectively (Levin et al.,
2006).
Hepatocyte
Inhibitors:
Growth
Factor/Scatter
Factor
The hepatocyte growth factor/scatter factor pathway
is another important mediator of glioma angiogenesis
(Abounader and Laterra, 2005). There has been
increased interest in targeting hepatocyte growth
factor/scatter factor and its tyrosine kinase receptor in
malignant glioma. Drugs in clinical development that
target this pathway include XL184 and AMG 102 (a
human monoclonal antibody against hepa tocyte growth
factor/scatter factor) (Chi et al., 2009).
Endothelial Cell Migration Inhibitors:
The ανβ3 and ανβ5 integrins (cell surface receptors)
promote endothelial cell migration and survival during
angiogenesis and represent attractive therapeutic targets
(Avraamides et al., 2008).
Cilengitide, the competitive ανβ3 and ανβ5 integrin
inhibitor, has demonstrated modest activity in recent
clinical trials in malignant glioma patients. In a phase II
trial, 81 patients with recurrent glioblastoma were
treated with cilengitide in two dose groups . Although the
drug was well tolerated, cilengitide exhibited modest
antitumor activity. A radiographic response of 13% and a
6-month progression-free survival of 15% were observed
in the higher dose group, with 2000 mg twice weekly
(Reardon et al., 2008).
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Chapter 4
Anti-angiogenic Therapy
Another phase II trial reported promising results
using cilengitide in newly diagnosed glioblastoma in
which 81 patients received either cilengitide in addition
to standard therapy (radiotherapy and chemotherapy) or
standard therapy alone. A 6-month progression-free
survival of 65.4% in patients treated with cilengitide was
significantly higher than 6-month progression-free
survival
with
standard therapy alone
(53.6%).
Cilengitide toxicity was minimal. Toxicity was similar in
both arms of the study (Stupp et al., 2007). In addition, a
clinical study observed good tumor penetration after
intravenous drug administration (Gilbert et al., 2007).
Based on these encouraging results, a multicenter
randomized phase III trial is underway using cilengitide
in newly diagnosed glioblastoma (Chi et al., 2009).
Metronomic Chemotherapy:
Metronomic
chemotherapy
is
a
conventional
chemotherapy administered at low doses.
It targets
mainly tumor vasculature and prevents tumor growth
(Kerbel and Kamen, 2004). Preclinical studies suggest
that certain conventional chemotherapeutic agents can
function as anti-angiogenic drugs when administered at
low doses on a continuous or frequent schedule (Gille et
al., 2005). In glioma animal models, metronomic
chemotherapy is an effective anti-angiogenic strategy
(Kim et al., 2006). Studies evaluating metronomic
chemotherapy reported favorable toxicity profiles, but no
significant survival benefits were observed (Chi et al.,
2009). Recently, two reports evaluating metronomic
chemotherapy in recurrent glioblastoma documented
modest gains in 6-month progression-free survival (Perry
et al., 2008). Clinical trials evaluating the addition of
bevacizumab to metronomic chemotherapy are ongoing
(Chi et al., 2009).
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Chapter 4
Anti-angiogenic Therapy
Current Challenges:
A number of issues remain unresolved concerning the
clinical use of anti-angiogenic drugs, including: (1)
toxicity profiles, (2) radiographic assessment, (3)
biomarkers, and (4) resistance (Chi et al., 2009).
Toxicity profiles:
The risks of hemorrhage and thrombosis have been
ongoing concerns with the use of antiangiogenic therapy.
Cumulative toxicity data indicate that major systemic
bleeding is rare, but risk of epistaxis is increased. The
intracranial hemorrhage risk appears t o be low, and
events are often asymptomatic (Norden et al., 2008).
Although some reports suggest an increased risk of
thromboembolic events in patients treated with
bevacizumab, this risk is difficult to assess, as patients
with glioblastoma have an intrinsically higher risk of
thrombosis (Chi et al., 2009).
It appears that some toxicities are shared by all
inhibitors of angiogenesis, but certain toxicities are
associated with specific classes of anti -angiogenic
agents. Toxicities common to both vascular endothelial
growth factor antibodies and vascular endothelial growth
factor receptors tyrosine kinase inhibitors include fatigue
and hypertension. Impaired wound healing is observed,
and may be problematic in treating glioblastoma patients
immediately after surgery (Lai et al., 2008). Hemorrhage
and gastro-intestinal perforation are less frequent . With
tyrosine kinase inhibitors, skin toxicity, hypertension,
diarrhea, and mucositis are more common, whereas
proteinuria is more frequent with bevacizumab. Other
rare but serious complications include myocardial
infarction, stroke, posterior leukoencephalopathy, and
thrombotic thrombocytopenic purpura (Chi et al., 2009).
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Chapter 4
Anti-angiogenic Therapy
Radiographic assessment:
Many studies reported high radiographic response
proportions in patients treated with anti-angiogenic
agents. Obtaining accurate assessment of response to
anti-angiogenic therapy is problematic in brain tumor
patients (Sorensen et al., 2008). Standard response
criteria currently in use for assessing treatment response
are dependent on contrast-enhancement on CT or MRI
(Macdonald
et
al.,
1990).
However,
contrastenhancement reflects vascular endothelial growth factor
mediated blood-brain barrier dysfunction and may not be
a reliable representation of the underlying tumor.
Moreover, anti-vascular endothelial growth factor agents
decrease permeability of cerebral vessels and diminish
the contrast enhancement making it difficult to
distinguish the anti-tumor effects of treatment from the
effects of these drugs on blood vessel permeability
(Batchelor et al., 2007).
Biomarkers:
There is a need for validated circulating or tissue
biomarkers that can accurately predict anti-angiogenic
efficacy and indicate progression. Several blood and
tissue components have been identified as candid ate
biomarkers (Duda et al., 2007). A recent study suggests
that vascular endothelial growth factor protein
expression in tumor tissue may be predictive for
radiographic response. This study reported tumor
expression of hypoxia-induced carbonic anhydrase 9
associated with shorter survival (Sathornsumetee et al.,
2008). In recurrent glioblastoma patients, radiographic
tumor progression during cediranib treatment was
associated with elevated levels of fibroblast growth
factor and circulating endothelial cells . That study and
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Chapter 4
Anti-angiogenic Therapy
others have shown that serum vascular endothelial
growth factor is significantly elevated in patients being
treated with anti- vascular endothelial growth factor
therapy. These serum markers have potential utility as
pharmacodynamic or pharmacokinetic biomarkers (Chi et
al., 2009).
Resistance:
Clinical data suggest that benefits gained from anti angiogenic agents will be short-lived. Almost all patients
treated with anti-angiogenic therapy progress during
treatment, as tumors finally acquir e resistance. After
failure of treatment with bevacizumab , tumor progression
is usually rapid (Quant et al., 2009).
Several mechanisms of resistance to angiogenesis
inhibitors have been proposed in glioblastoma. Tumors
may induce revascularization by acti vating alternate
proangiogenic pathways (Bergers and Hanahan, 2008).
In recurrent glioblastoma, patients who progressed
during cediranib treatment had elevated levels of
circulating mediators of alternative proangiogenic
pathways (Batchelor et al., 2007). A second mechanism
of resistance involves the recruitment of vascular
progenitor cells and proangiogenic monocytes from the
bone marrow (Murdoch et al., 2008). Hypoxia, by
inducing hypoxia-inducible factor attracts to the tumor a
heterogeneous population of bone marrow-derived cells
that facilitate neovascularization (Du et al., 2008).
Other studies raise the possibility that tumors may not
develop resistance per se. Treatment failure may be due
to inability of anti-vascular endothelial growth factor
drugs to control the continued growth of the tumor (Chi
et al., 2009).
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Chapter 4
Anti-angiogenic Therapy
Future Directions:
Current evidence suggests that anti-angiogenic
therapy has clinical benefits including steroid-sparing
effects and increased progression-free survival. A
definite survival advantage has yet to be established.
Several issues and obstacles remain in the clinical
development of anti-angiogenic agents. Prospective
randomized controlled trials that use survival as an
endpoint will be required to determine whether antiangiogenic strategies increase survival of patients.
Furthermore, clinical trials with correlative imaging and
molecular studies will be critical to overcome challenges
(Chi et al., 2009).
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Chapter (5)
Stereotactic
Radiosurgery
Chapter 5
Stereotactic Radiosurgery
Stereotactic Radiosurgery
There are three fundamental strategies of delivering
the ionizing radiation to any intracranial neoplasm:
(1)
Stereotactic radiosurgery (2) Stereotactic radiotherapy
(3) Fractionated radiation therapy . The essential
difference between these strategies is in number of
fractions or doses that the physician uses to deliver the
total dose to the patient. In stereotactic radiosurgery, the
total dose is typically delivered in one fraction, although
the current definition permits a maximum of 5 fractions.
In stereotactic radiotherapy and in fractionated radiation
therapy, tens of fractions may be required, depending on
the total dose to be delivered, and they are differentiated
only by the fact that stereotactic radiotherapy is
delivered stereotactically (Barnet et al., 2007).
Stereotactic (stereotaxis) refers to the technology of
precisely localizing a target within the 3 dimensional
space (Barnet et al., 2007).
Radiosurgery signifies any kind of application of
ionizing radiation energy aiming at precise and complete
destruction of chosen target structures containing healthy
and/or
pathological
cells,
without
significant
concomitant or late radiation damage to adjacent tissues
(Larsson, 1992).
Stereotactic radiosurgery is performed by Cobalt -60
gamma source unit (Gamma Knife) or by Linear
accelerators system. Masks or cranial pin frames provide
immobilization. Preoperative imaging is paramount
(Thng et al., 1999).
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Chapter 5
Stereotactic Radiosurgery
Gamma knife and Linear accelerator systems are
radiosurgical
equipments
to
treat
predetermined
intracranial targets through the intact skull without
damaging the surrounding normal brain tissue. The
technical developments allow more precise control of
intracranial lesions and offer more conformal dose plans
for irregular lesions (Vesper et al., 2009).
Current Radiosurgical Techniques:
Gamma Knife (Models A, B, C, 4-C, and
PFX®):
Gamma Knife uses multiple fixed cobalt sources
inside a helmet, which are arranged to intersect at a
given point. A head frame is attached to the patient’s
skull and the patient is positioned within the helmet so
that the target corresponds to the focal point of the
device (Fig. 10) (Mayberg and Vermeulen, 2007). The
latest model, Leksell Gamma Knife® PERFEXION®
(PFX®), was released in 2006 (Fig. 11) (Niranjan et al.,
2007).
Fig . 1 0 . Ga m ma - K n i fe p r i ncip le ( Ma yb erg a nd Ve rm eu le n, 2 0 0 7 ).
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Chapter 5
Stereotactic Radiosurgery
The disadvantages of Gamma Knife may be (1) the
need to attach the frame to the skull, (2) limitation of
treatment to intracranial lesions above the foramen
magnum, and (3) the inability to fractionate or divide the
dose (Mayberg and Vermeulen, 2007).
Fig . 1 1 . P ho to gr ap h o f the wo r ld ’s first P erfeXio n Gamma Knife (Elekta
Instrument AB , Sto ckho lm, Swed en) installed at T imo ne University
Ho sp ital ( Rég is et a l., 2 0 0 9 ) .
Linear accelerator-Based Radiosurgery:
There are many Linear accelerator based systems
such as XKnife®, Linear Accelerator Scalpel®,
Novalis®, the Peacock System®, and CyberKnife®
(Niranjan et al., 2007).
CyberKnife uses a linear accelerator attached to an
industrial robot to precisely define the target tissues and
adjacent critical structures, and create a highly
conformal dose (Fig. 12). CyberKnife radiosurgery can
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Chapter 5
Stereotactic Radiosurgery
be utilized for lesions anywhere in the body. The patient
does not need rigid frame fixation and the doses can be
fractionated to provide additional safety. On the other
hand, CyberKnife has not been in widespread use as
many years as Gamma Knife and follow-up data is not as
well developed for this modality (Mayberg and
Vermeulen, 2007).
A comparison of Gamma
CyberKnife Radiosurgery:
Gamma Knife
Knife
and
CyberKnife
Pa tient
selectio n
intr acr anial tar gets
intracranial
targets
and
body
Ta rg et
identifica tio n
b y sur geo n
b y surgeo n o r o nco lo gist
Ta rg et
lo ca liza tio n
r igid ster eo tactic fr ame
mask o r fid ucials
Ima g ing
MRI , CT , P E T
CT
Pa tient
po sitio ning
r o b o tic p o sitio ning o f head
in a co llimato r helmet
ro b o tic
p o sitio ning
Cyp erKnife
aro und
p atient
Do se pla nning
mo stl y b y sur geo n
mo stl y b y p hysici s t
Do se deliv ery
2 0 1 Co -6 0 b eams
light -weight
accelerato r
Ra dia tio n
1 .2 5 MV p ho to ns
6 MV p ho to ns
Accura cy
0 .3 mm
0 .7 mm
Trea tmen t time
single
d ay
p r o ced ure
( fr ame p lacement, imaging,
d o se p lanning, r ad iatio n
d eliver y)
Multip le d ay p ro ced ure
(mask
or
fid ucial
p lacement, imaging, d o se
p lanning, treatment)
of
the
linear
Ta ble. 1 . A co mp a r iso n o f Gamma Knife and Cyb erKnife Rad io surgery
( Nira nja n et a l., 2 0 0 7 ) .
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Fig . 1 2 . T he Cyb er Knife : co nsists o f a linear accelerato r mo unted o n a six axis ro b o tic manip ulato r that p ermits a wid e range o f b eam o rientatio ns
(Nira nja n et a l., 2 0 0 7 ) .
Radiosurgery for Brain Metastasis:
Stereotactic radiosurgery with a Gamma Knife or a
linear accelerators system is now being used as primary
management or booster treatment with whole brain
radiation therapy in an increasing number of patients
with
brain metastasis,
both radiosensitive
and
radioresistant, single and multiple. Radiosurgery became
relatively routine, rather than special, ‘high -tech’
treatment (Yamamoto, 2007).
Although the size limitation on treatable lesions is
crucial in radiosurgery, tumor control rates of 90%, or
even better, can be expected if 1–4 lesions are irradiated
with a peripheral dose of 20 gray (Gy) or more. In such
cases,
true
recurrence
is
extremely
rare.
Postradiosurgical MRI reveals disappearance of the
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Chapter 5
Stereotactic Radiosurgery
tumors and complete cure, as confirmed by autopsy. The
incidence of radiosurgery-related complications, i.e.
symptomatic radionecrosis of the normal brain, is no
more than 3.0%. Prolonged survival cannot be expected
because survival duration depends primarily on nonbrain
lesions (including the primary tumor). 80–90% of
patients die of causes other than brain tumor progression
(Pollock and Brown, 2002).
Controversy persists as to whether stereotactic
radiosurgery should be combined with whole brain
radiation therapy. Although some reports have supported
combining treatment with whole brain radiation therapy
to achieve optimal tumor control and survival periods
(Chidel et al., 2000), others have questioned usefulness
of whole brain radiation therapy (Sneed et al., 2002).
Neither the survival rate nor the local tumor recurrence
rate differs significantly between groups with vs. without
whole brain radiation therapy (Yamamoto, 2007).
Retrospective analysis of 619 patients underwent
linear accelerators-based stereotactic radiosurgery for
1569 brain metastases between 1989 and 2006 revealed
encouraging results. The median survival was 7.9
months. 1- and 2-year survival probabilities were 0.36
and 0.14, respectively. Factors that were associated with
improved survival are: 1) female sex, 2) younger age, 3)
higher Karnofsky performance status, 4) controlled
primary tumor, 5) absence of systemic metastases , 6)
asynchronous presentation of brain metastases , 7) fewer
brain metastases, 8) smaller total volume of brain
metastases, 9) surgery prior to radiosurgery, and 10)
multiple radiosurgical treatments . Local control was
achieved in 84.3% of all lesions treated . Linear
accelerator-based stereotactic radiosurgery was a safe
and effective treatment for patients with brain
metastases. Selection of patients who are likely to
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benefit most from stereotactic radiosurgery is complex
and treatment decisions should be based on the entire
clinical picture (Swinson and Friedman, 2008).
Frameless
stereotactic
radiosurgery
( linear
accelerators system) has been used for treatment of 53
patients with 158 brain metastases. The radiation doses
were delivered in a single fraction ( dose range, 12-22
Gy). The overall survival rate was 70% at 6 months, 44%
at 1 year, 29% at 18 months, and 16% at 24 months.
Local control was achieved in 90% at 6 months, 80% at
12 months, 78% at 18 months, and 78% at 24 months.
Local control tended to be improved in lesions treated
with >or=18 Gy and for lesions <0.2 cm. Adverse events
occurred in 5 patients (9.6%). No evidence of
mistargeting of the radiation isocenter (Breneman et al.,
2009).
Number of Lesions That Can Be Treated:
‘How many tumors can and should be treated?’ has
long been a central question in the field of stereotactic
radiosurgery for brain metastases. In a linear
accelerators system, the upper tumor number limit is
generally considered to be 4–5 lesions in a single session
due to mainly the prolonged procedure time. In Gamma
Knife radiosurgery, the maximum number of lesions that
can be treated in a 1-day session is 30 or even slightly
more. If a patient has > 40 lesions, it is recommended
that the procedure be divided into two sessions, 1 day
apart, with the patient keeping the stereotactic head
frame on overnight (Yamamoto, 2007).
A comprehensive review found no correlation
between lesion number, even in patients with eight or
more lesions, and survival (Boyd and Mehta, 1998).
Gamma Knife radiosurgery for multiple metastases
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produces survival rates similar to those achieved using
Gamma Knife for single metastasis (Suzuki et al., 2000).
Presently, most patients can be treated using a Gamma
Knife in one frame position, without replacing the frame,
as was previously required (Yamamoto et al., 2003).
Stereotactic radiosurgery is beneficial for carefully
selected end-stage patients with 10 or more brain
metastases. Even those patients can maintain good
performance status for a major portion of their remaining
life (Yamamoto, 2007).
Advantages of Gamma Knife Radiosurgery
over Whole Brain Radiation Therapy:
Gamma Knife radiosurgery is superior to whole brain
radiation therapy for several reasons: (1) Only a brief
hospital stay is necessary, (2) Higher control rates and
earlier symptom palliation can be achieved, (3) All
observable lesions on MRI can be treated, even if such
lesions are radioresistant, (4) Other treatments, such as
radiation therapy for other parts of the body, surgery and
chemotherapy, need not be interrupted, (5) The
availability of an alternative treatment for brain
metastases allows whole brain radiation therapy to be
reserved for subsequent treatment attempts. Whole brain
radiation therapy should be postponed until it is
absolutely necessary, (6) Gamma Knife radiosurgery can
be repeated, even after whole brain radiation therapy.
Whole brain radiation therapy usually cannot be
repeated, (7) Patients never lose all of their hair, (8) A
very low incidence of dementia can be expected
(Yamamoto, 2007).
Analysis of the outcomes and cost-effectiveness of
gamma Knife radiosurgery and whole brain radiation
therapy was done over a period of 5 years in 156 patients
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Stereotactic Radiosurgery
with multiple brain metastases The mortality rate was
lower for Gamma Knife than for whole brain radiation
therapy. The median survival time for Gamma Knife and
whole brain radiation therapy was 9.5 months and 8.3
months, respectively. Gamma Knife resulted in higher
cost-effectiveness than whole brain radiation therapy for
treating multiple brain metastases (Lee et al., 2009).
Safety of Gamma Knife
Multiple Metastases:
Treatment
for
The cumulative irradiation doses to the normal brain
were calculated based on the treatment protocols for 92
patients who underwent Gamma Knife radiosurgery for
10 or more metastases. The doses to the whole normal
brain were estimated to be 4.0 –6.0 J in most patients
(range 2.2–11.9 J). These estimates confirm that
cumulative irradiation doses for patients with numerous
radiosurgical targets do not exceed the threshold level
associated with necrosis. In fact, the symptomatic
complication rate is very low (1%). Two thirds of
patients died less than 12 months after treatment, i.e. one
third of patients lived long enough to experience
radiation-induced complications. The incidence of such
complications was 3% in the latter special patient group
(Yamamoto et al., 2002).
Radiosurgery as Post-operative Irradiation:
Very little information is available on Gamma Knife
radiosurgery as an alternative to post-operative
irradiation. Surgical removal followed by Gamma Knife
radiosurgery was used in 23 patients. Gamma Knife
irradiation was delivered to t he cavity remaining after
tumor removal. Local tumor control rate of 78.3% was
comparable to the rates of local control achieved with
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Stereotactic Radiosurgery
surgery followed by whole brain radiation therapy.
Therefore, radiosurgery can be used as post -operative
irradiation instead of whole brain radiation therapy,
which has several disadvantages (Yamamoto, 2007).
Radiosurgery for Brain Meningiomas:
Surgeons have traditionally preferred to use Gamma
Knife radiosurgery as an adjunctive treatment modality
after surgical resection or for patients who are at high
risk for operative morbidity or mortality. Multiple
studies demonstrated the efficacy and safety of Gamma
Knife with tumor control rates ranging from 60 to 100%
depending on the proportion of atypical or malignant
meningiomas (Lee et al., 2002). Given the benefit of
radiosurgery, Gamma Knife has been increasingly used
to treat patients as a primary therapy based on imaging
criteria only (Flickinger et al., 2003).
Radiosurgery of meningiomas at the skull base
represents particular concern to the vascular and neural
structures that are often embedded within or around the
meningioma. It was found that the motor cranial nerves
within the cavernous sinus are particularly less sensitive
to radiation doses used in radiosurgery while the sensory
nerves appear to be more sensitive (Lee et al., 2002).
Radiosurgery was performed in almost 1,000 patients
with meningiomas at the University of Pittsburgh. This
treatment modality can be performed either as an adjunct
to surgical resection or as a primary procedure. Gamma
Knife provides 5- and 10-year tumor control rates of 93%
for benign meningiomas. The 5 -year control rate for
atypical and malignant meningiomas was 83 ± 7% and 72
± 10%, respectively. The complication rate remains low.
The incidence of adverse radiation effect ranged from 5.7
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Chapter 5
Stereotactic Radiosurgery
to 16% and was gradually reduced with the advent of
MRI and lower dosing (Lee et al., 2007).
Stereotactic radiosurgery was used in patient group
consisted of 972 patients with 1045 intracranial
meningiomas. The overall control rate for patients with
benign meningiomas was 93%. In those without previous
histological confirmation tumor control was 97%.
However, for patients with atypical and malignant
meningiomas, the tumor control was 50% and 17%,
respectively. Delayed resection after radiosurgery was
necessary in 5% of patients at a mean of 35 months. After
10 years, benign meningiomas were controlled in 91%
and in those without histology 95% were controlled.
None of the patients developed a radiation -induced
tumor. The overall morbidity rate was 7.7%.
Radiosurgery provided high rates of tumor control or
regression in patients with benign meningiomas. This
study confirms the role of radiosurgery as an effective
management choice for patients with small to mediumsized symptomatic, newly diagnosed or recurrent
meningiomas of the brain (Kondziolka et al., 2008).
CyberKnife was used in a series of 199 benign
intracranial meningiomas. The tumor volume decreased
in 36 patients, was unchanged in 148 patients, and
increased in 7 patients. Three patients underwent
repeated radiosurgery, and 4 underwent operations. One
hundred fifty-four patients were clinically stable. In 30
patients, a significant improvement of clinical symptoms
was obtained. In 7 patients, neurological deterioration
was observed. The procedure proved to be safe. Clinical
improvement seems to be more frequently observed with
the CyberKnife than in other previous linear accelerator
experience (Colombo et al., 2009).
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Chapter 5
Stereotactic Radiosurgery
Radiosurgery for Brain Gliomas:
There are several papers summarizing the exper ience
of radiosurgery in gliomas. In 16 cases of low-grade
astrocytomas treated with Gamma Knife, it was found
disappearance of tumor in 50% and decrease or static
tumor size in 31% of cases (Barcia et al., 1994). Gamma
Knife was used in 8 cases of pilocytic astrocytoma and 5
cases of low-grade astrocytoma in children. In pilocytic
astrocytoma, the tumor either disappeared or decreased
in 7 cases. In low-grade astrocytoma, the tumor either
disappeared or decreased in 2 cases (Grabb et al., 1996).
Stereotactic radiosurgery with a linear accelerator
system and standard radiation therapy were used in 32
patients with glioblastoma multiforme underwent tumor
debulking or biopsy. The 12-month survival was 37%
(Masciopinto et al., 1995). The impact of stereotactic
radiosurgery on the survival of patients with malignant
gliomas was evaluated and found that the 2 -year and
median survival was 45% and 96 weeks, respectively.
Patients treated with stereotactic radiosurgery had a
significantly improved 2-year and median survival
(Sarkaria et al., 1995).
Stereotactic radiosurgery represents an alternative or
supplementary treatment modality to conventional
surgery in small-volume low-grade astrocytomas
especially in deep-seated critical locations. There is also
evidence for beneficial effect of stereotactic radiosurgery
on the survival of patients with high-grade glioma
(Szeifert et al., 2007).
Out of a series of brain tumor patients treated at the
Lars Leksell Center for Gamma Knife Surgery, 74
astrocytomas were selected. In astrocytoma grade I; the
tumor either disappeared or decreased in 60% and
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Chapter 5
Stereotactic Radiosurgery
increased in 40% of cases following Gamma Knife. Best
results occurred when the pretreatment volume was < 3
cm3. The mean volume of tu mors with response to the
treatment was 2.7 cm3. In astrocytoma Grade II; the
tumor either disappeared or decreased in 58.8%,
remained unchanged in 12.5% and increased in 31.3%
cases. In astrocytoma Grades III and IV; a decrease in
the tumor size was observed in 22% of cases with
complete disappearance in 2 cases. There was no change
in the tumor volume of 28.5% and increase in size was
noticed in 45% of cases. The mean survival time interval
was 26 months. At 5 years, 25% of patients were live
(Szeifert et al., 2007).
In another recent study, stereotactic radiosurgery was
well tolerated in glioblastoma treatment. There was no
difference in survival whether stereotactic radiosurgery
is delivered upfront or at recurrence, so the treatment
should be individualized for each patient. Future studies
are needed to identify patients most likely to respond to
stereotactic radiosurgery (Biswas et al., 2009).
Radiosurgery for Pituitary Adenomas:
Stereotactic radiosurgery is a safe and highly
effective treatment for patients with pituitary adenomas.
Radiosurgery provides control of tumor growth in nearly
all cases and hormone normalization in the majority of
secretory tumors (Mayberg and Vermeulen, 2007).
Numerous studies documented that more than 95% of
pituitary adenoma show either shrinkage or stabilization
after stereotactic radiosurgery. Biochemical remission is
possible in approximately 80% of properly selected
patients. The time to endocrinal normalization typically
ranges from 1 to 5 years. Since the effects of
radiosurgery are gradual, it is effective for persistent or
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Chapter 5
Stereotactic Radiosurgery
recurrent tumors after surgery or for patients with high
risk for open surgical procedures (Pollock, 2007).
Patients with persistent or recurrent hormonal
overproduction now typically undergo stereotactic
radiosurgery. Patients stop all pituitary suppressive
medications for 4–6 weeks before radiosurgery. At
radiosurgery, every attempt is made to provide a
maximum tumor margin dose that exceeds 20 Gy while
still limiting the radiation dose to the optic apparatus to
less than 12 Gy. In this manner, biochemical remission is
possible for approximately 80% of patients. The majority
of patients achieve hormonal normalization 12–24
months
after
stereotactic
radiosurgery.
Also,
radiosurgery has replaced radiation therapy for patients
with recurrent or progressive non functioning pituitary
adenomas (Pollock, 2007).
Between 1997 and 2007, 347 patients with secretory
pituitary adenomas were treated with Gamma Knife
radiosurgery. In 47 of these patients some form of prior
treatment such as transsphenoidal resection or
craniotomy and resection was done. In the others,
Gamma Knife served as the primary treatment modality.
Of the 68 patients with adrenocorticotropic hormone secreting adenomas, 89.7% showed tumor volume
decrease or remain unchanged and 27.9% experienced
normalization of hormone level. Of the 176 patients with
prolactinomas, 23.3% had normalization of hormone
level and 90.3% showed tumor volume decrease or
remain unchanged. Of the 103 patients with growth
hormone-secreting adenomas, 95.1% experienced tumor
volume decrease or remain unchanged and 36.9% showed
normalization of hormone level. None of the patients in
the study experienced injury to the optic apparatus or
had other neuropathies related to Gamma Knife (Wan et
al., 2009).
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Chapter 5
Stereotactic Radiosurgery
Complications of Radiosurgery:
Treatment complications have been reported from the
early experience of 2 Canadian radiosurgery programs.
Patients were accumulated until August , 2007, and a
total of 973 patients were included i n this report. During
the radiosurgical procedure, 19 patients (2%) suffered
anxiety or syncopal episodes, and 2 patients suffered
acute coronary events. Treatments were incompletely
administered in 12 patients (1.2%). Severe pain was a
delayed complication; 8 patients suffered unexpected
headaches, and 9 patients developed severe facial pain.
New motor deficits developed in 11 patients. Four
patients required shunt placement for symptomatic
hydrocephalus, and 16 patients suffered delayed
seizures. Gamma Knife radiosurgery is a minimally
invasive treatment modality for many intracranial
diseases. Treatment is not risk free, and some pati ents
will develop complications that will decrease as
institutional experience matures. Expanding availability
and indications necessitate discussion of these risks with
patients (Vachhrajani et al., 2008).
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Chapter (6)
Chemotherapy
Chapter 6
Chemotherapy
Chemotherapy
Chemotherapy has played primarily an adjuvant role
in the treatment of brain tumors because of efficacy
limitations related to drug-delivery issues and inherent
tumor chemoresistance (Cairncross et al., 1998).
The blood-brain barrier is mediated by tight junctions
between endothelial cells of brain vasculature,
preventing the penetration of large molecules with poor
lipid solubility or tight protein binding. Even in areas in
which there is a breakdown of the blood-brain barrier
(areas of contrast enhancement on MRI), variable intraand peri-tumoral hydrostatic pressures from cerebral
edema make drug delivery at useful concentrat ions
challenging (Calatozzolo et al., 2005).
Recent developments in chemotherapy of brain tumors
include the combination of cytotoxic, cytostatic and
targeted therapies. Multitargeted compounds that
simultaneously affect multiple signaling pathways are
increasingly employed (Soffietti et al., 2007).
Cytotoxic Chemotherapy:
During the past three decades, thousands of patients
with malignant gliomas have been entered on adjuvant
chemotherapy trials. The most commonly used
chemotherapeutic drugs have been nitrosoureas, either
alone as carmustine or in combination with other agents
as in PCV that include procarbazine, lomustine, and
vincristine. Nitrosureas were the mainstay of adjuvant
therapy. Carmustine (BCNU) and orally available
lomustine (CCNU) are liposoluble drugs. Studies of
carmustine documented a modest 10–15% benefit in
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Chapter 6
Chemotherapy
survival at 18 months, but no difference in median
survival or survival at 12 or 24 months. Major toxicities
include fatigue, nausea, myelosuppression, and doserelated pulmonary fibrosis (Walker et al., 1980).
Two meta-analyses of clinical trials for high -grade
gliomas have demonstrated therapeutic benefits from
addition
of
nitrosourea-based
chemotherapy
to
radiotherapy. Glioma meta-analysis was performed on
individual patient data from 12 randomized trials and
showed a modest, but significant prolongation of
survival associated with the addition of chemotherapy.
An absolute increase in 1-year survival of 6% (from 40
to 46%) and in 2-year survival of 5% (from 15 to 20%)
was found (Soffietti et al., 2007).
Temozolomide is an oral alkylating agent with ability
to cross an intact blood-brain barrier and excellent
toxicity profile (Newlands et al., 1997). Temozolomide’s
favorable toxicity profile makes it the preferred therapy.
Temozolomide has demonstrated antitumor activity as a
single chemotherapeutic agent in recurrent glioma after
conventional therapies with response rates ranging from
35% for anaplastic astrocytomas to 5% for glioblastomas
(Brada et al., 2001).
The Food and Drug Administration (FDA) approved
temozolomide for the treatment of recurrent anaplastic
astrocytomas only, whereas the European authorities
approved the drug for both anaplastic astrocytomas and
glioblastoma.
The
approved
schedule
(‘standard
regimen’) was a dose of 150– 200 mg/m2/day for 5 days
of every 28-day cycle. On the basis of experimental data
showing a synergism between temozolomide and
radiation (Van Rijn et al., 2000), and the availability of
an extended continuous schedule of the drug for up to 7
weeks (Brock et al., 1998), Stupp et al. conducted a pilot
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Chapter 6
Chemotherapy
phase II trial for newly diagnosed GBMs using
conventional fractionated radiotherapy with concomitant
temozolomide (75 mg/m2/day), followed by up to 6
cycles of adjuvant temozolomide using the standard
regimen. This regimen showed promising clinical
activity including median survival of 16 months and 2year survival rate of 31% (Stupp et al., 2002).
Why did this trial show a greater benefit with
temozolomide than all the previous trials with
nitrosoureas? Several explanations can be put forward.
First, most patients had favorable prognostic factors (i.e.
age under 70 years, good performance status, total or
partial resection). Second, temozolomide is better
tolerated and may be more active than nitrosoureas.
Third, the concurrent administration of the drug during
radiotherapy, by utilizing the radiosensitizing effect of
temozolomide, may have played an important role in
improving the outcome (DeAngelis, 2005).
Multi-institutional trial enrolled 120 patients with
recurrent glioblastoma, anaplastic astrocytoma, or
anaplastic oligodendroglioma. An init ial oral dose of 200
mg/m2 of temozolomide was followed by 9 consecutive
doses of 90 mg/m2 every 12 hours. Treatment cycles
were repeated every 28 days. Doses were escalated to
100 mg/m2 twice daily in the absence of unacceptable
toxicity or were reduced if unacceptable toxicity
occurred. For glioblastoma, anaplastic astrocytoma, and
anaplastic oligodendroglioma patients, resp ectively, the
median progression-free survival was 4.2 months, 5.8
months, and 7.7 months, whereas the median overall
survival was 8.8 months, 14.6 months, and 18 months.
The overall response rate for glioblastoma, anaplastic
astrocytoma, and anaplastic oligodendroglioma patients
was 31%, 46%, and 46%, respectively. Twice-daily
dosing may enhance the efficacy of temozolomide in
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Chapter 6
Chemotherapy
treatment of recurrent gliomas without increasing
toxicity. This regimen compares favorably with other
dosing schedules of temozolomide reported in the
literature (Balmaceda et al., 2008).
Other alkylating agents that penetrate the blood-brain
barrier include procarbazine, thiotepa, and busulfan, but
they have little activity in gliomas as single agents.
Platinum compounds are used with modest results for
recurrent disease, but they also have poor blood-brain
barrier penetration (Warnick et al., 1994). Plant
alkaloids have poor brain entry and little activity in
gliomas. Vincristine is used most often in combination
with procarbazine and lomustine for oligodendroglioma.
Etoposide was studied in combination with carboplatin
and as monotherapy with modest results (Franceschi et
al., 2004).
Efforts
to
maximize
efficacy
of
cytotoxic
chemotherapy by overcoming blood-brain barrier
limitations include intra-arterial delivery, blood-brain
barrier disruption and implantation of polymer-based
drug delivery vehicles directly into the tumor bed. Dose
intensification intended to increase drug gradients across
the blood-brain barrier for improved penetration is often
faced by the added systemic toxicity. Intra-arterial
administration allows higher concentrations to be
delivered to brain parenchyma without first-pass
metabolism (Ashby et al., 2001). Combining Intraarterial administration with osmotic blood-brain barrier
disruption improves treatment responses, especially in
chemosensitive brain tumors, such as germ cell tumors
and CNS lymphoma. However, increased neurotoxicity is
prohibitive (Fortin et al., 2005).
The chemosensitivity of primary CNS lymphoma is
exceptional. Addition of chemotherapy to standard
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Chapter 6
Chemotherapy
radiotherapy had an appreciable impact on tumor
response and patient survival. Combined -modality
regimens prolong survival compared with radiotherapy
alone and are the mainstay of treatment of primary CNS
lymphoma. They consist of high-dose methotrexate-based
combination chemotherapy and radiotherapy. These
regimens result in impressive survival benefit with
median overall survival ranging from 25 to 60 months.
Methotrexate is typically infused over several hours to
optimize CSF penetration and is given weekly or every 2
weeks. High-dose methotrexate-based regimens are given
in multiple cycles with the goal of inducing a
radiographic complete response. This regimen is
followed by whole brain radiation therapy (Mohile and
Abrey, 2007).
Molecularly Targeted Therapy:
Trials of molecularly targeted drugs as monotherapy
for gliomas were disappointing, with some potential
benefit when used in combination with hydroxyurea or
temozolomide. Combinations of multitargeted therapy
are increasingly the focus of clinical trials (Kreisl,
2009).
Everolimus,
sirolimus,
and
temsirolimus
are
mammalian target of rapamycin inhibitors that have been
studied as single agents and combination therapy with
epidermal growth factor receptor inhibitors (Doherty et
al., 2006). Novel agents like enzastaurin and tamoxifen
inhibit protein kinase C (Fine et al., 2008). Tamoxifen
showed only moderate efficacy in clinical practice with
no improvement in the median survival time . Enzastaurin
has shown promising efficacy in the clinical practice,
with a 29% radiographic response rate in patients with
recurrent high-grade gliomas. Progress with enzastaurin
was stopped when a phase III trial was stopped
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Chapter 6
Chemotherapy
prematurely as significant survival benefits were not
seen (Mercer et al., 2009).
Vorinostat, one of the histone deacetylases inhibitors,
was used in the treatment of glioma and showed potential
benefit. Pretreatment with vorinostat can make glioma
cells more susceptible to chemotherapy and radiation
(Chinnaiyan et al., 2005). In a phase II trial of
vorinostat in recurrent glioblastoma, the drug was well
tolerated and anti-tumor efficacy was noted; progressionfree survival for 6 months was 23% (Galanis et al.,
2007). Other deacetylase inhibitors (e.g. romidepsin,
LBH589, and valproic acid) are being developed
clinically for the treatment of glioblastoma (Mercer et
al., 2009).
The interpretation of “molecularly targeted therapy”
can be widened to include therapies that are conjugates
of a cytotoxic factor (radioisotope, toxin or standard
drug) and a tumor-specific vector (an antibody or other
tumor-specific ligand). Most of this work is done in the
setting of convection-enhanced delivery. This allows
delivery of large molecular weight drugs that are unable
to penetrate the blood-brain barrier. Two randomized
phase III trials have investigated convection-enhanced
delivery of toxin conjugates; transferrin-conjugated
diphtheriae toxin (Weaver and Laske, 2003) and
interleukin
13-conjugated
pseudomonas
exotoxin
(Kunwar et al., 2007).
The invasive nature of the treatment and associated
neurotoxicity make this modality appropriate for only
selected patients with tumors of size and location
physically amenable to convection-enhanced delivery
(Kreisl, 2009).
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Chapter 6
Chemotherapy
Combination of Cytotoxic
‘Cytotoxic Synergy’:
Agents
One can combine drugs with either similar or
different mechanism of action. Nitrosoureas (carmustine,
lomustine, fotemustine) and temozolomide are both
alkylating agents with independent activity in gliomas
(Gerson, 2002).
Preclinical models observed a synergistic activity of
carmustine and temozolomide, but did not identify the
optimal sequence and schedule to maximize antitumor
activity and minimize toxicity. Different schedules have
been employed clinically, including administrati on of
both drugs on day 1 (Plowman et al., 1994). This
regimen resulted in significant myelotoxicity, without
any additive antitumor activity in phase I and II studies
(Prados et al., 2004).
The best tolerated sequence seems represented by
carmustine (on day 1) followed by temozolomide (days
1–5) (Hammond et al., 2004). As neoadjuvant therapy in
inoperable glioblastomas, this combination has exhibited
promising activity (Barrie et al., 2005). To avoid
overlapping toxicities, the combination occurs between
locally administered carmustine (‘Gliadel Wafers’) and
temozolomide, and seems attractive as serum carmustine
levels are undetectable after gliadel implant (Olivi et al.,
2003) and the results of a phase I study are encouraging
(Gururangan et al., 2001). Moreover, there seems to be
a rationale for sequencing Gliadel Wafers and
temozolomide + radiotherapy in resected patients with
newly diagnosed glioblastomas: first, to kill with
carmustine the resistant tumor cells in the postoperative
period; second, to exploit a synergism between
carmustine and radiation during the first weeks of
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Chapter 6
Chemotherapy
radiotherapy. A phase II study of radiation with
concomitant and adjuvant temozolomide in patients with
newly diagnosed supratentorial malignant glioma who
have undergone surgery with carmustine wafers insertion
is ongoing; preliminary results have been reported, and
include a 1-year survival rate of 63%. If the final results
confirm the efficacy and safety of this combination, a
phase III study comparing carmustine wafers and
temozolomide + radiotherapy versus temozolomide +
radiotherapy would be warranted (Soffietti et al., 2007).
The combination of lomustine, temozolomide and
radiotherapy has yielded promising survival data (2 -year
survival rate of 44.7%), and acceptable toxicit y in
patients with newly diagnosed glioblastomas (Herrlinger
et al., 2006).
Carmustine and cisplatin have been suggested to be
synergistic, and moreover cisplatin has a well-known
radiation sensitizer effect that can persist long after
administration, thus being attractive to be incorporated
in chemotherapy regimens in the pre-radiation setting.
Despite these premises and impressive response rates in
phase II trials (Grossman et al., 1997), continuous
infusion of carmustine and cisplatin before radiotherapy
in newly diagnosed malignant gliomas has not led to
improvements in survival and having relatively high
toxicity (Grossman et al., 2003).
Alkylating
agents
are
ideal
candidates
for
combination therapy with irinotecan, as they have
different mechanisms of action and different systemic
toxicities. Irinotecan is a topoisomerase I inhibitor with
substantial activity in glioma cell cultures and human
glioblastoma xenografts. After intravenous injection, it is
metabolized in the liver into the active metabolite SN-38
that has some ability to cross the blood-brain barrier
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Chemotherapy
(Hare et al., 1997). Clinical trials using irinotecan in
patients with recurrent malignant gliomas reported
response rates ranging from 2 to 15%, and extended
progression-free survival at 6 months as high as 56%
(Batchelor et al., 2004).
Carmustine and irinotecan display a scheduledependent synergistic activity against glioma cell s, with
maximal
activity
achieved
when
administering
carmustine before irinotecan (Castellino et al., 2000).
To date, carmustine and irinotecan for patients with
malignant gliomas have not been proven to be superior to
irinotecan alone, and may be associated with increased
pulmonary toxicity (Reardon et al., 2004). To enhance
the blood-brain barrier penetration and reduce the
systemic toxicity, a locally delivered irinotecan (by
biodegradable wafers) could be coupled with systemic
carmustine (Storm et al., 2004).
Another alternative option is represented by
temozolomide combined with irinotecan that has
demonstrated encouraging preclinical activity (Patel et
al., 2000). A phase I trial with escalating doses of
irinotecan and a standard dose of temozolomide in
recurrent glioblastomas has shown a response rate of
14%, with progression-free survival for 6 months of
27%. A number of phase II studies are ongoing (Soffietti
et al., 2007).
Combination of cytotoxic, cytostatic
and targeted molecular agents:
The rationale for combining cytotoxic and cytostatic
agents lies in the different mechanism of antitumor
activity and non-overlapping side effect profiles.
Cytostatic agents may have anti-angiogenic, anti- 105 -
Chapter 6
Chemotherapy
invasion/migration
and
(Drappatz and Wen, 2004).
differentiating
properties
Thalidomide inhibits endothelial cell proliferation and
basic fibroblast growth factor-induced angiogenesis, and
has immunomodulatory effects. To enhance its modest
activity as single agent in gliomas, thalidomide has been
combined with cytotoxic agents such as carmustine and
temozolomide. The combination of carmustine and
thalidomide has been evaluated in patients with
predominantly recurrent glioblastomas. The response rate
was 24% and the progression-free survival for 6 months
was 27%. These results compared favorably with
carmustine alone (Fine et al., 2003). The combination of
temozolomide and thalidomide (both oral agents) has
yielded interesting results. The median survival of newly
diagnosed glioblastoma patients (73 weeks) was better
than that after radiation therapy alone, but similar to that
after radiotherapy and adjuvant nitrosoureas (Chang et
al., 2004). Lenalidomide is an analog of thalidomide,
which has increased anti-angiogenic activity and fewer
side effects and is under investigation (Soffietti et al.,
2007).
Temozolomide and cilengitide, an integrin antagonist,
could be synergistic in inhibiting the increased
expression of αvβ3 integrin after radiotherapy, thus
interfering with the radiation-induced upregulation of
angiogenesis (Wick et al., 2002).
Cyclooxygenase-2 is often upregulated in gliomas and
there is increasing evidence that cyclooxygenase-2
inhibitors may block angiogenesis and growth. Clinical
trials combining cyclooxygenase-2 inhibitors, such as
celecoxib or rofecoxib, with irinotecan or temozolomide
have been performed with some activity (Soffietti et al.,
2007).
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Chemotherapy
High-dose tamoxifen, a protein kinase C inhibitor, has
shown some activity both alone and in combination with
carboplatin or procarbazine. Protein kinase C inhibitors
as tamoxifen, staurosporine, hypericin and calphositin C
act as chemo-sensitizers, but association of high-dose
tamoxifen and continuous temozolomide in recurrent
gliomas is not effective and relatively toxic (Soffietti et
al., 2007).
Enzastaurin is an inhibitor of protein kinase -β2 with
potent anti-angiogenic activity in preclinical models. A
phase II trial in patients with recurrent gliom as has
shown promising activity (14 objective radiographic
responses out of 79 evaluable patients, i.e. 18% ) (Fine et
al., 2005). A phase III trial of enzastaurin compared with
standard therapy with lomustine in patients with
glioblastoma at first relapse, failed to meet its efficacy
endpoints, but significant radiographic responses and
excellent toxicity profile were observed (Fine et al.,
2008).
Marimastat is a low-molecular weight peptide that
inhibits matrix metalloproteinases which degrade the
extracellular matrix, and thereby enable tumor invasion
and migration. In-vitro studies of marimastat showed a
significant inhibition of invasion of glioma cell lines
(Tonn et al., 1999). Single-agent marimastat failed to
improve survival in patients with glioblastoma or
gliosarcoma following surgery and radiotherapy (Levin
et al., 2006).
Two phase II trials tested marimastat in combination
with
temozolomide
in
patients
with
recurrent
glioblastoma and anaplastic gliomas, respectively. In the
first study, the combination resulted in a progressionfree survival for 6 months that exceeded the historical
control group by 29%. Joint and tendon pain were the
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Chemotherapy
major side effects, occurring in 47% of patients (Groves
et al., 2002). In the second study, the regimen was
roughly equivalent to single-agent temozolomide and was
associated with additional toxicity (Groves et al., 2006).
Differentiating agents, such as retinoids, induce the
differentiation of malignant cells into mature cells, and
can also suppress cell proliferat ion and induce apoptosis.
Retinoids have been studied in clinical trials with good
tolerance but modest success (Drappatz and Wen, 2004).
The
combination
of
13-cis-retinoic
acid
with
temozolomide in gliomas (Jaeckle et al., 2003) and both
of them with concurrent radiotherapy, has yielded results
not superior to that obtained with conventional therapy
(Butowski et al., 2005).
Many targeted molecular agents are currently being
evaluated in the treatment of gliomas (Reardon et al.,
2006). Studies in colorectal cancer showed that targeted
molecular agents can enhance the activity of cytotoxic
chemotherapy, being the combinations far more active
than single agents alone (Hurwitz et al., 2004).
Farnesyltransferase inhibitors inhibit the activity of
enzyme implicated in the Ras/MAPK signaling pathway.
Such inhibitors as tipifarnib and lonafarnib are being
tested in glioblastoma clinical trials, either alone or with
radiation and/or temozolomide (Soffietti et al., 2007).
Upfront Chemotherapy for
Diagnosed Malignant Gliomas:
Newly
A phase III trial compared radiotherapy +
temozolomide with radiotherapy alone in 573 patients
with newly diagnosed gliomas from 85 institutions in 15
countries. Patients were randomized to receive radiation
alone (60 Gy) or with concurrent temozolomide, 75
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Chemotherapy
mg/m2 daily, followed by 6 months of adjuvant treatment
at 150 to 200 mg/m2 on 5- out of 28-day schedule.
Survival benefit was observed for chemotherapy added to
radiation in the initial management of patients with
glioblastoma. The median survival was 14.6 months
after radiotherapy and temozolomide compared with 12.1
months after radiotherapy alone, with a 37% reduction in
the risk of death. The 2-year survival rate was 26.5%
with the combined treatment while it was 10.4% with
radiotherapy alone. The combination of radiotherapy and
temozolomide was associated with a significant
improvement in median survival and also it was well
tolerated in all subgroups of patients. Many if not most
neuro-oncologists extend the adjuvant therapy to at least
1 year, anticipating inevitable recurrence for most
patients (Stupp et al., 2005). More recent evidence
supports temozolomide’s effect as a radiosensitizer (Van
Nifterik et al., 2007).
Efforts to improve on initial therapy for malignant
glioma patients include ongoing and anticipated studies
that depend on concurrent chemo-radiation with
temozolomide. Novel radiosensitizers, neoadjuvant
regimens, and temozolomide combination trials are all
being investigated (Kreisl, 2009).
Mechanisms of chemoresistance:
A number of mechanisms of resistance to
chemotherapeutic drugs have been reported in brain
tumors, but to date only a few have known clinical
relevance (Bredel et al., 2006).
Mechanisms of intrinsic chemoresistance are poorly
understood. The most important mechanism of resistance
in malignant gliomas is based on the activity of the
enzyme O6-methylguanine DNA methyltransferase which
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Chemotherapy
causes resistance to some alkylating chemotherapeutic
agents. This enzyme repairs the DNA damage induced by
alkylating agents. A correlation of tumor O6methylguanine DNA methyltransferase levels with the
outcome of glioma patients has been reported. Patients
with low O6-methylguanine DNA methyltransferase
levels (i.e. those with a reduced capacity to repair DNA
damage) displayed significantly longer survivals and/or
higher response rates during treatment with carmustine
or temozolomide (Kreisl, 2009).
Some data suggest that epidermal growth factor
receptor
overexpression/amplification
could
be
associated with resistance to alk ylating agents (Leuraud
et al., 2004).
Fortunately, advances in cancer therapeutics have
afforded novel agents directed at tumor -specific
oncogenic targets (Kreisl, 2009).
Future Directions:
Concomitant chemo-radiotherapy followed by singleagent adjuvant treatment with the alkylating agent
temozolomide is the current standard of care for the
patients
with
glioblastomas.
The
concomitant
administration of chemotherapy with radiotherapy, as
well as the early introduction of chemotherapy, appears
to be the key to the improving outcome. Better
understanding
of
the
molecular
pathways
of
carcinogenesis, particularly gliomagenesis, will allow
development
of
specifically
targeted
therapies.
Correlative molecular studies, now included in most
ongoing trials, will enhance our understanding of this
disease and allow for rapid further improvement in
outcome (Stupp et al., 2007).
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Chemotherapy
Although conventional chemotherapeutic agents
continue to be developed to reduce toxicity and/or
improve efficacy, the remarkable advances made in
knowledge of tumor biology in the past decade have
shifted the focus onto novel agents that target molecular
changes crucial for tumor proliferation or survival. These
selective agents are predicted to be less toxic to normal
cells and it is anticipated that they will be more effective
than currently used nonspecific chemotherapeutic agents.
The toxicity and efficacy of these novel agents is
currently being assessed with brain tumors. Ultimately,
if these novel therapies prove effective, their role in
combination with established chemotherapeutic agents
will need to be assessed (Gottardo and Gajjar, 2008).
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Chapter (7)
Endocrinal
Therapy
Chapter 7
Endocrinal Therapy
Endocrinal Therapy
Pituitary Tumors:
Pituitary tumors represent about 15% of the primary
intracranial neoplasms and the hormone-secreting tumors
account for about 30% of all pituitary tumors (Patil et
al., 2009).
The medical approach to pituitary adenomas has been
greatly improved since the availability of dopamine
agonists such as: bromocriptine, cabergoline and
quinagolide, and availability of somatostatin analogues
such as: lanreotide slow release and autogel, and
octreotide long-acting repeatable (Colao et al., 2009).
The efficacy of dopamine agonists in prolactin
secreting adenomas and efficacy of somatostatin
analogues in growth hormone and thyroid stimulating
hormone secreting adenomas is well established . More
recently, data are accumulating suggesting a potential
therapeutic role of dopamine agonists also in patients
with adrenocorticotrophic hormone secreting and
clinically non-functioning pituitary adenomas (Colao et
al., 2009).
Available
Dopamine
Somatostatin Analogues:
Agonists
and
The class of dopamine agonists includes ergot
derivatives (bromocriptine, pergolide, metergoline,
lisuride, terguride, and cabergoline) and non ergot
derivatives (Quinagolide). The ergot alkaloids have a
wide spectrum of pharmacological effects . These effects
are mainly responses mediated by noradrenaline,
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Chapter 7
Endocrinal Therapy
serotonin and dopamine receptors. Within the class of
non ergot derivatives, quinagolide is the most active and
when compared to bromocriptine, it was about 35 times
more potent (Colao et al., 2002).
Octreotide was the first commercially available
somatostatin analogue and was formulated for
subcutaneous administration. It has a high affinity for
somatostatin receptors. Octreotide is administered with
multiple daily injections (2-4) and its growth hormone
suppressive effect lasts at most 5 h after injection
(Lamberts et al., 1996). Octreotide is also available in a
long-acting repeatable formulation. The active compound
is encapsulated in microspheres of a biodegradable
polymer. After intramuscular injection, the drug levels
begin to rise over 7–14 days and remains plateau for 20–
30 days (Lancranjan et al., 1996). Dosing every 4 weeks
is typical (McKeage et al., 2003). The pharmacological
effect of the drug can be manipulated by varying the
dose from 10 to 30 mg with a fixed dosing interval of 28
days. It can be used up to 40 mg every 28 days (Colao et
al., 2007).
Lanreotide slow release is a medium-acting
somatostatin analogue. The drug is encapsulated in
microspheres that provide prolonged release over 10 –14
days after intramuscular administration (Colao et al.,
1999). Lanreotide slow release is provided in a 30 and 60
mg dosage (the latter only in Italy) and the
pharmacological effect is manipulated by changing the
dosing interval among every 7, 10, or 14 days (Freda,
2002). More recently another long-acting formulation,
lanreotide autogel, has become available in many
European countries and in United States (Caron et al.,
2006). Autogel forms a slow-release aqueous gel that can
be administered subcutaneously and its pharmacological
effect can be manipulated by varying the dose from 60,
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Endocrinal Therapy
90, or 120 mg with a fixed 28 days ad ministration
schedule or by varying the interval between injections
between 28–56 days maintaining the dose of 120 mg
(Lombardi et al., 2008).
Pasireotide (SOM 230) is another somatostatin
analogue that underwent experimental investigation. It
has high affinity for somatostatin receptors (Bruns et al.,
2002). Available data about pasireotide is only related to
its effect on growth hormone level (Van der Hoek et al.,
2004). However, in a study in mice bearing growth
hormone/prolactin secreting adenomas, pasireotide
induced greater tumor shrinkage than octreotide (Fedele
et al., 2007).
Dopamine Agonists and Somatostatin
Analogues in Pituitary Adenomas:
1. Prolactin Secreting Adenomas:
Bromocriptine was introduced into clinical practice as
the first medical treatment for prolactinomas (Gillam et
al., 2006). It has a relatively short elimination half -life,
so that it is usually taken 2 or 3 times daily, although
once daily may be effective in some patients. Generally,
the therapeutic doses are in the range of 2.5–15 mg/day
and most patients are successfully treated with 7.5 mg or
less. However, doses as high as 20–30 mg/day may be
necessary for patients who demonstrate resistance. For
microprolactinomas bromocriptine is successful in 80–
90% of patients in normalizing serum prolactin level,
restoring gonadal function and shrinking tumor mass
(Colao et al., 2002).
For macroprolactinomas normalization of serum
prolactin level and tumor mass shrinkage occur in about
70% of patients treated with bromocriptine. In most
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Endocrinal Therapy
patients, headache and visual field defects improve
dramatically within days after the first administration of
bromocriptine with gonadal and sexual function
improving even before complete normalization of serum
prolactin level (Colao et al., 2009).
Cabergoline is widely used to treat prolactinomas.
Cabergoline treatment normalized prolactin level in 86%
of 425 patients (Verhelst et al., 1999). Generally, the
dose of cabergoline at the start of therapy was 1
mg/week in patients with macroprolactinomas a nd 0.5
mg/week in those with idiopathic hyperprolactinaemia or
microprolactinomas. Remarkable tumor shrinkage was
observed in patients with microprolactinomas; 12–24
months treatment with cabergoline induced more than
20% decrease of baseline tumor size in more than 80% of
cases with complete disappearance of the tumor mass in
26–36% of cases. The tumor shrinking effect is very
rapid and improvement of visual field defects can be
detected even after the administration of the first tablet
(Colao et al., 2000).
The superiority of cabergoline over bromocriptine
was supported by a comparative retrospective study by
Di Sarno et al. and by the evidence of further tumor
shrinkage in patients previously intolerant or resistant to
bromocriptine and in those already responsive to it (Di
Sarno et al., 2001).
A
recommendation
in
patients
with
large
macroadenomas, is to begin cabergoline treatment (as
well as any other dopamine agonists) with very low
doses as in some very responsive tumors treatment can
be associated with remarkable early tumor shrinkage
leading to rhinorrhea that need surgical intervention
(Cappabianca et al., 2001). In patients chronically
treated with cabergoline, withdrawal of treatment for as
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Endocrinal Therapy
long as 5 years was not associated with tumor re-growth.
In this study, patients with macroadenomas extending
into critical areas such as cavernous sinuses or cerebral
areas were excluded (Colao et al., 2003).
Quinagolide is one of the dopamine-agonists used to
treat prolactinomas. Several studies demonstrated that
once-daily
quinagolide
in
women
with
hyperprolactinaemia reduced prolactin level and tumor
size and relieved gonadal dysfunction thereby restoring
fertility (Gillam et al., 2006). Tumor mass was reduced
by at least 30% in 21 of 26 patients with
macroprolactinomas. Rare dissociation between prolactin
control and tumor shrinkage can be encountered (Colao
et al., 2009).
It is expected that pasireotide could have some role in
treating patients with prolactinomas resistant to
dopamine agonists, but there are no clinical data at
present. Experimental data recently published showed
that pasireotide produced a dose-dependent inhibition of
prolactin release similar to that of cabergoline in
dopamine agonists-sensitive prolactinomas (Fusco et al.,
2008).
2. Growth Hormone Secreting Adenomas:
Dopamine agonists are primarily effective only in
those growth hormone secreting tumors that co-secrete
prolactin or that exhibit immunostaining for prolactin
(Melmed et al., 2002). In a collection of 28 series
including
over
500
patients
with
acromegaly,
bromocriptine produced a symptomatic improvement in
up to 70% of the patients but lowered growth hormone
levels below 5 μg and induced tumor shrinkage in only
10–15% of patients (Jaffe and Barkan, 1994).
In
contrast, it was reported tumor shrinkage in 13 of 21
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Endocrinal Therapy
patients with a tumor reduction of 50% in 5 growth
hormone/prolactin secreting adenomas (Abs et al., 1998).
In the last decade, several studies have indicated that
some tumor shrinkage is achieved using somatostatin
analogues as first-line treatment (Colao et al., 2009).
Many studies have analyzed tumor shrinkage with
somatostatin analogues therapy. The definition of tumor
shrinkage differed across studies but overall, 217 of 478
patients (45%) had a reduction in tumor size. In patients
treated first-line with somatostatin analogues, 51% had
tumor shrinkage while in patients treated after
unsuccessful surgery and/or radiation, 27% had tumor
shrinkage (Bevan, 2005). Similarly, it was reported that,
an approximately 50% decrease in pituitary mass is
achieved when a somatostatin analogues is used
exclusively or before surgery or radiotherapy. In 14
studies including 424 patients, the results showed that
36.6% of patients receiving primary somatostatin
analogue therapy for acromegaly experienced a
significant reduction in tumor size (Melmed et al.,
2005).
In 99 patients treated with lanreotide slow release
and octreotide long-acting repeatable for 12 months, the
tumor shrinkage was absent (<25% of baseline size) only
in 22.2% of patients, mild (25–50% of baseline size) in
31.1%, moderate (50– 75% of baseline size) in 30.3%
and notable (>75% of baseline size) in 14.1% of p atients.
There was no difference in the amount of tumor
shrinkage with the two analogues (Colao et al., 2006).
In a study including patients treated only with
somatostatin analogues up to 18 years, the mean
reduction in tumor volume was 43% (range 13 –97%) and
shrinkage >20% was obtained in 72% of the patients
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Chapter 7
Endocrinal Therapy
(Maiza et al., 2007). A very recent study has confirmed
that, results obtained with lanreotide slow release and
autogel and with octreotide long-acting repeatable are
similar (Murray and Melmed, 2008).
In a study for 2 years of continuous treatment with
octreotide long-acting repeatable, increased doses up to
40 mg every 28 days increased the chance to control
growth hormone level and increased the rate of tumor
shrinkage. A significant shrinkage (>25%) was found in
52.9% of patients after 12 months when they received 30
mg every 28 days and in all patients after 24 months
when treated with 40 mg every 28 days. No data are
currently available with
lanreotide autogel. A
preliminary experience in 26 patients treated first-line
with this somatostatin analogue formulation had tumor
shrinkage after 6 months of treatment (Colao et al.,
2009).
It has been demonstrated that both somatostatin
receptors and dopamine receptors are frequently
coexpressed in adenomas from acromegalic patients and
thus immunohistochemistry may determine receptor
expression in pituitary adenomas to select patients
responsive to different treatments (Ferone et al., 2008).
The combination treatment with somatostatin
analogues and dopamine agonists could be beneficial to
better suppress growth hormone level and also on tumor
shrinkage but results on tumor shrinkage are lacking. The
effect of somatostatin analogues on tumor shrinkage is
reversible as demonstrated by tumor re-growth after
stopping somatostatin analogues (Colao et al., 2009).
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Chapter 7
Endocrinal Therapy
3. Thyroid Stimulating Hormone Secreting
Adenomas:
This adenoma histotype is rare and frequently at
diagnosis tumors are macros presenting with mass effect
symptoms with variable symptoms of hyperthyroidism
(Beck-Peccoz et al., 1996). The medical treatment of
thyroid stimulating hormone secreting adenomas depends
mainly on administration of somatostatin analogues, as
dopamine agonists failed to persistently block hormone
secretion in almost all patients and caused tumor
shrinkage only in those with co-secretion of thyroid
stimulating hormone and prolactin (Kienitz et al., 2007).
Somatostatin inhibits thyroid stimulating hormone
secretion both in physiological conditions and in thyroid
stimulating hormone secreting adenomas as well as
thyroid stimulating hormone secreting adenomas express
somatostatin receptors. So, somatostatin analogues are a
very efficient treatment in patients with thyroid
stimulating hormone secreting pituitary tumors to
improve the clinical signs, the hormone levels and to
produce tumor shrinkage (Fischler and Reinhart, 1999).
Octreotide given subcutaneously induced an acute
thyroid stimulating suppression . In more than 90% of
thyroid stimulating hormone secreting adenomas,
octreotide subcutaneous suppressed thyroid stimulating
hormone secretion and in about 50% of cases adenoma
size was reduced (Chanson et al., 1993). Octreotide
treatment was also considered useful preoperatively as it
allowed an easier tumor removal as it produces tumor
shrinkage (Beck-Peccoz et al., 1996).
Another multicenter study reported treatment with
octreotide long-acting repeatable in thyroid stimulating
hormone secreting adenomas. Eleven patients received
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Endocrinal Therapy
octreotide subcutaneous (at dosages of 200–900
μg/daily) first and then octreotide long-acting repeatable
(at 20 mg, every 28 days) after 4 weeks, both
formulations significantly reduced thyroid stimulating
hormone and thyroid hormone levels without causing
significant side effects (Caron et al., 2001). The dose of
octreotide needed to achieve thyroid stimulating
hormone normalization was reported to be lower than
that needed to suppress growth hormone in growth
hormone secreting adenomas (Colao et al., 2003).
Lanreotide slow release treatment was similarly
shown to suppress plasma thyroid stimulating hormone
level and to normalize thyroid hormones with no
significant change in adenoma size (Kuhn et al., 2000).
In five cases with thyroid stimulating hormone
secreting pituitary adenomas, the hormone levels were
successfully normalized and remained normal throughout
the treatment period. The dosage of octreotide longacting repeatable, or lanreotide slow release, required to
normalize thyroid stimulating and thyroid hormone
levels was indeed low (300 μg/day, 10 mg every 28 days,
and 30 mg every 14 days, respectively) compared with
dosages generally required in patients with growth
hormone secreting adenomas, however, dosage should be
titrated
on
the
basis
of
individual
patients’
responsiveness and tolerance (Colao et al., 2003).
4. Adrenocorticotrophic Hormone Secreting
Adenomas:
The medical treatment of adrenocorticotrophic
hormone secreting adenoma is reserved for patients with
unsuccessful surgery (Pivonello et al., 2008) even after
repeated pituitary surgery that is efficacious in
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Endocrinal Therapy
approximately two-thirds (50–70%) of patients (Biller et
al., 2008).
In long-term studies with bromocriptine, disease
remission was confirmed in only a small minority of
patients (Miller and Crapo, 1993).
A small, short-term study suggests that cabergoline at
dosages of 2–3.5 mg/week may be effective (Pivonello et
al., 2004). An extension study of this latter enrolling 20
patients after unsuccessful surgery, demonstrated that
after 3 months of treatment, 75% of patients had
normalization of free urinary cortisol that in 50% of
them was maintained for 12 months (Colao et al., 2009).
Tumor shrinkage after 6 months of cabergoline treatment
was observed in 4 of 10 patients responsive to the
treatment (Pivonello et al., 1999).
The use of cabergoline is still experimental and more
data are required before proposing this treatment as an
official therapy for adrenocorticotrophic hormone
secreting tumors (Colao et al., 2009).
The possible role of somatostatin analogues has also
been re-evaluated; pasireotide has been demonstrated to
reduce adrenocorticotrophic hormone secretion in cell
culture of corticotroph tumor (Hofland et al., 2005).
No definitive data are available on clinical trials, just
a preliminary experience on very short -term treatment
that looks encouraging (Boscaro et al., 2005). These data
on the effectiveness of specific dopamine agonists and
somatostatin analogues suggest that their combination
may also be a possible therapeutic a pproach (Colao et
al., 2009).
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Chapter 7
Endocrinal Therapy
5. Non Functioning Adenomas:
Bromocriptine was used in non-functioning adenomas
with disappointing results (Bevan et al., 1986).
Quinagolide efficacy in the treatment of these tumors
was tested in a few studies and significant tumor
shrinkage was documented only in 4 out of 12 reported
patients (Ferone et al., 1998).
Cabergoline was administered to 10 patients with
non-functioning adenomas and significant adenoma
shrinkage was found only in 2 out of 10 patients with
non-functioning adenomas (Colao et al., 2000). In 18
patients with remnant non-functioning adenomas, 12
months of cabergoline treatment induced tumor shrinkage
in 56%. Tumor shrinkage was associated with dopamine
D2 receptor expression (Pivonello et al., 2004).
The results of chronic octreotide treatment were
controversial; it was reported to induce a rapid
improvement of headache and visual disturbances,
without any change in tumor volume (Warnet et al.,
1997). Decrease of tumor volume by 30±4% was reported
in some patients with non-functioning adenomas treated
with a combined octreotide + cabergoline treatment.
There are no data on the effects of somatostatin
analogues, octreotide or lanreotide slow release or
autogel in non-functioning adenomas (Andersen et al.,
2001).
Although first-line therapy of non-functioning
adenomas is surgery, only 35.5% are considered cured
after surgery. Conventional radiotherapy is reported to
delay tumor regrowth and causes hypopituitarism in all
patients after 10 years. Therefore, there is a need for an
additional treatment in the majority of non-functioning
adenomas patients. Both somatostatin analogues and
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Endocrinal Therapy
dopamine agonists were found to be of some efficacy in
selected patients with non-functioning adenomas, with
the latter drugs being significantly more effective in
reducing tumor volumes. However, no placebo -controlled
long-term studies are available to suggest the use of
somatostatin analogues or dopamine agonists or a
combination of them (Colao et al., 2008).
Meningiomas:
It has been demonstrated that most of meningiomas
express hormone receptors on their cell membranes
(Marosi et al., 2008). Actually, up to 90% of
meningiomas express progesterone receptors, while 30 to
48% express estrogen receptors (Korhonen et al., 2006).
It has been reported that the expression of the
progesterone receptors alone in meningiomas indicates a
favourable clinical and biological outcome. A lack of
progesterone receptors or the presence of estrogen
receptors correlates with an increasing potential for
aggressive clinical behaviour, progression and recurrence
of meningiomas (Pravdenkowa et al., 2006).
Epidemiological and immunohistochemical data have
led to some attempts of treatment with anti -hormonal
therapies for patients with progesterone receptors
positive meningioma (Strik et al., 2002).
Mifepristone is oral anti-progesterone commonly used
in treatment of estrogen receptors positive breast cancer
with a significant benefit in global survival. Mifepristone
inhibits the activity of progesterone receptors by
complex mechanisms (Edwards et al. 2000). The use of
progesterone antagonists in the palliation of meningioma
has been discussed for more than 10 years (Strik et al.,
2002).
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Endocrinal Therapy
The only prospective study on this topic was
conducted on 160 patients in whom 80 patients were
treated with mifepristone 200 mg and 80 patients were
treated with placebo for a median duration of 10 months.
The trial was prematurely closed. No difference was
observed between the two arms in terms of time to
progression, but 55% of patients had stable disease, 1%
of patients had partial response and no patient achieved
complete response (Newfield et al. 2001).
Feasibility of hormonal therapy was assessed in 28
patients with unresectable meningioma treated with oral
mifepristone 200 mg/day and oral dexamethasone 1
mg/day for the first 14 days. With a median duration of
therapy of 35 months, minor responses (improved visual
field examination or improved CT or MRI scan) were
noted in 8 patients, 7 of whom were male or
premenopausal female, which can result in significant
clinical benefit in this subgroup of patients (Grunberg et
al., 2006).
In a phase II evaluation of hormonal therapy by
tamoxifen (an orally active selective estrogen receptors
modulator that competitively binds to estrogen receptors
and inhibits oestrogen effects) in unresectable or
refractory meningiomas, only 5% of patients achieved
partial response, 10% had minor response that was of
short duration, 32% remained stable for a median
duration of more than 31 months while 53%
demonstrated progression. A definite recommendation
for the use of tamoxifen in refractory meningiomas could
not be made (Goodwin et al. 1993).
Brain Tumors and Steroids:
A major cause of death in glioblastoma patients (more
than 60% of cases) is brain herniation due to cerebral
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Chapter 7
edema and
2009).
Endocrinal Therapy
increased
intracranial
pressure
(Altaha,
Corticosteroids are usually indicated in any patient
with brain tumor with symptomatic peri-tumoral edema.
Dexamethasone is used most commonly as it has little
mineralocorticoid activity and, possibly, a lower risk for
infection and cognitive impairment compared with other
corticosteroids (Batchelor and DeAngelis, 1996).
Vasogenic edema associated with brain tumors results
from increased capillary permeability and causes
neurologic dysfunction by exerting pressure on brain
structures. This leads to headache with nausea, emesis
and exacerbation of seizures; if severe, edema can result
in herniation and death (Papadopoulos et al., 2001).
The mechanism of action of corticosteroids is not
well understood. It has been argued that the anti-edema
effect is due to reduction of the permeability of tumor
capillaries by causing dephosphorylation of the tight
junction component proteins (Drappatz et al., 2007).
Dexamethasone reduces the tumor-associated edema
in patients with brain metastases or primary brain tumor
as illustrated by CT studies (Sturdza et al., 2008).
Dexamethasone produces symptomatic improvement
within 24 to 72 hours. Generalized symptoms, such as
headache and lethargy, tend to respond better than focal
ones. Improvement on CT and MRI studies often lags
behind clinical improvement (Drappatz et al., 2007).
Side effects of corticosteroids were dose-dependent,
while the degree of neurologic improvement was
independent of the dose. It is therefore generally
accepted that corticosteroid dose should be titrated to the
minimal dose needed to relieve symptoms. The usual
starting dose is a 10 mg load, followed by 16 mg per day
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Endocrinal Therapy
in patients who have significant symptomat ic edema.
Lower doses may be effective, especially for less severe
edema. The dose may be increased up to 100 mg per day
if necessary (Drappatz et al., 2007). The time to peak
concentration for an oral tabl et is 1-2 hours. The plasma
half-life is about 2-4 hours but its biologic half-life is 36
to 54 hours (Sturdza et al., 2008).
Special care should be given to the tapering of the
corticosteroid dose. Decreasing the dose by 25% every
4–5 days is a rational approach. In patients who have
required corticosteroids for more than 2 weeks, the
“steroid withdrawal syndrome” may occur (Rosenfeld
and Pruitt, 2007). There is no standard recommendation
regarding steroid dose used in patients with cerebral
metastases, prior, during or following palliative
radiotherapy (Sturdza et al., 2008).
A number of important aspects should be considered
when prescribing steroids to maximize quality of life: (I)
the lowest effective dose possible of corticosteroids
should be used; (II) regarding peri-tumoral edema, treat
the patient and not the MRI image (clinically
asymptomatic edema does not require steroid treatment);
(III) to reduce insomnia linked to steroids , avoid
prescribing it in the evening; (IV) because of the risk of
adrenal insufficiency following abrupt discontinuation ,
corticosteroids should be tapered progressively unless
steroids have been administered for two weeks or less
(Stupp et al., 2008).
Corticosteroid intake leads t o a wide range of side
effects. Side effects of corticosteroids include endocrine
disorders such as Cushing’s syndrome and disturbances
of the blood sugar level ranging up to diabetes mellitus,
muscular weakness, increasing risk of infectious
diseases, gastrointestinal complications such as ulcers or
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Endocrinal Therapy
bleeding, atrophic changes of skin, and hematological
and psychiatric disorders (Sturdza et al., 2008). Longer
duration of treatment (more than 3 weeks), higher doses,
and hypoalbuminemia are associated with greater toxicity
(Drappatz et al., 2007).
The side effects associated with corticosteroids are
the driving force to search for alternative therapies for
cerebral edema. Corticotropin-releasing factor reduces
peritumoral edema by a direct effect on blood vessels
through Corticotropin-releasing factor 1 and 2 receptors.
Phase I/II trials of this agent suggest that it is relatively
well tolerated. Several phase III trials are in progress
examining the efficacy of this drug in the treatment of
acute and chronic peritumoral edema . Preliminary studies
suggest that cyclooxygenase-2 (COX-2) inhibitors may
be effective in treating cerebral edema but further
clinical studies using cyclooxygenase-2 inhibitors have
been delayed due to the cardiovascular complications of
this class of drugs. Inhibitors of vascular endothelial growth
factor or inhibitors of its receptors reduce tumor-related
edema. These classes of drugs eventually may prove
more effective and less toxic alternatives to
corticosteroids (Drappatz et al., 2007).
Future Endocrinal Therapy:
Thyroid hormone plays a major role in normal brain
maturation and affects the development of astrocytes.
Increasing evidence has suggested that aberrant
expression of thyroid hormone receptors isoforms could
be associated with tumorigenesis. Thyroid hormone
receptors expression was compared between low grade
and high grade astrocytomas. A study demonstrated for
the first time that thyroid hormone receptors isoforms
are indeed expressed in human astrocytomas. The
expression of thyroid hormone receptors isoforms is
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Endocrinal Therapy
correlated to the malignancy grading of astrocytomas.
The frequency of thyroid hormone receptors α1 or α2
expression significantly decreas ed with the grade of
malignancy. However, the frequency of thyroid hormone
receptors β1 expression significantly increased wit h the
grade of malignancy. This result provides insight into the
potential use of hormonal therapy for brain tumors that
overexpress or underexpress thyroid hormone receptors
(Hwang et al., 2008).
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Chapter (8)
Gene & Viral
Therapies
Chapter 8
Gene & Viral Therapies
Gene and Viral Therapies
Advances in understanding and controlling genes and
their expression have set the stage to alter genetic
material to prevent or fight disease with brain tumors
being among one of the first human malignancies to be
targeted by gene therapy. All proteins are coded for by
DNA and most neoplastic diseases ultimately result from
the expression or lack of one or more proteins (e.g.,
coded by oncogenes or tumor suppressor genes,
respectively). Therefore, diseases could be treated by
expression of the appropriate protein in the affected cells
(Asadi-Moghaddam and Chiocca, 2009).
Currently available treatments for brain tumors
necessitate the development of more effective tumor selective therapies. The use of gene therapy for brain
tumors is promising as it can be delivered in situ and
selectively targets tumor cells while sparing the adjacent
normal brain tissue (Germano and Binello, 2009).
Gene therapy is an experimental treatment that
involves introducing genetic material (DNA or RNA)
into cells, and it has made important advances in the past
decade. Within this short time span, it has moved from
the conceptual laboratory research stage to clinical
translational trials for brain tumors (Asadi-Moghaddam
and Chiocca, 2009).
Two crucial considerations in gene therapy relate to:
(1) what gene should be delivered for expression, and (2)
how to deliver it. In its simplest form, gene therapy is
the process by which either defective or missing genes
are replaced, or new genes for new functions are
introduced. For this purpose, the genetic material is
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Gene & Viral Therapies
coupled to additional regulatory sequences (e.g.,
promoters and enhancers) and is packaged inside a gene
delivery vehicle to enable transfer and expression of the
gene product inside the cell (Fig. 13) (AsadiMoghaddam and Chiocca, 2009).
The first step of gene therapy involves gene delivery
to facilitate the expression of the therapeutic gene in the
interior of a cell. The simplest method is the direct
introduction of therapeutic DNA into target cells by
physical (i.e., electroporation) or chemical techniques
(i.e., lipofection). This approach still remains limited in
its application, as it is relatively inefficient, it can be
used only with certain tissues and requires large amounts
of DNA (Anwer, 2008).
The next difficulty for the foreign genetic material is
that once within the cell, it must escape intrac ellular
degradation to enter the nucleus to be expressed
(Lechardeur and Lukacs, 2006). Therefore, gene
delivery systems (vectors) were designed to protect the
genetic material (Fig. 13). An ideal vector needs to meet
three criteria: (1) it should protect the transgene (the
transferred gene) against degradation by nucleases in the
extracellular matrix; (2) it should bring the transgene
across the plasma membrane and then into the nucleus of
the target cells; and (3) it should have no harmful effects
(Bergen et al., 2008).
Vectors for Gene Therapy:
Gene delivery can be accomplished using different
vectors. Historically, viral vectors were the first used.
Cell-based transfer and synthetic vectors have
subsequently been developed and seem to be promising
gene delivery methods (Germano and Binello, 2009).
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Gene & Viral Therapies
(1) Viral Vectors:
Viruses used in brain tumor therapy can be divided
into two categories:
A) Replication-incompetent viruses (viral vectors)
that can not replicate and they act as mere vectors for
gene transfer. In this case, the vector is derived from a
virus from which all or most of the viral genes have been
removed to minimize the virus-mediated toxicity. Two
replication-incompetent
viruses,
retrovirus
and
adenovirus, were studied in clinical trials (AsadiMoghaddam and Chiocca, 2009).
B) Replication-competent viruses (oncolytic viruses)
that infect then replicate and lyse tumor cells with or
without gene transfer and these viruses are used in the
oncolytic virotherapy. In this case, selected viral genes
are deleted or mutated so that viral targeting and/or
replication can occur selectively in the tumor cells. Four
replication-competent viruses; herpes simplex virus,
replicating adenovirus, reovirus and Newcastle disease
virus, were studied in clinical trials (Asadi-Moghaddam
and Chiocca, 2009).
The most effective way to transfer DNA into somatic
cells remains the use of viral vectors. Gene transfer
using viral vectors has been carried out in numerous
clinical trials. Retrovirus and adenovirus are the most
studied vectors for brain tumors. Retroviruses were the
first used vectors. Adenoviral vectors offer several
theoretical advantages over retroviruses . These include
increased efficiency and ability to transcribe genes
without insertion in the host genome, th ereby eliminating
the risk of insertional mutagenesis (Germano and
Binello, 2009).
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Chapter 8
Gene & Viral Therapies
(2) Cell-based Vectors:
Neural stem cells, neural progenitor cells, embryonic
stem cells derived astrocytes , bone marrow-derived stem
cells, mesenchymal stem cells, endothelial progenitor
cells, and fibroblasts were used for gene transfer
(Germano and Binello, 2009).
(3) Synthetic Vectors:
Liposomes are the most studied nanoparticles for gene
delivery. Liposomes are spherical vesicles with a
membrane composed of a phospholip id and cholesterol
bilayer, and can deliver and release DNA and drugs
(Benítez et al., 2008). Liposomes become an attractive
alternative to viral vectors. Their main advantage
includes safety and lack of immunogenicity but they have
low efficiency. Liposomal vectors have been used to
deliver therapeutic genes in rodents and in clinical trials
for brain tumors (Germano and Binello, 2009).
Tumor
cell
nucleus
mRNA
Gene + Vector
Fig . 1 3 . Mechanism o f vecto r -med iated gene therap y: a vecto r b ind s to the
cell memb rane then ent er s the cell. T he gene then travels to the nucleus,
where it b eco mes acti ve. I n the nucleus, the gene b eco mes transcrib ed into
mRNA then mRNA b eco mes p r o tein, and the d esired effect o ccurs. In this
case, the d esir ed effect was to cause ap o p to sis o f tumo r cell s b y
intro d ucti o n o f an a p o p to tic g en e ( Asa d i - Mo g ha d d a m a nd Chio cca , 2 0 0 9 ).
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Chapter 8
Gene & Viral Therapies
Approaches of Gene Therapy:
Five gene therapy approaches are currently being
explored: (1) Suicide gene therapy (pro-drug activating
gene therapy or chemotherapy-sensitizing gene therapy);
(2) Tumor suppressor gene therapy; (3) Immunogene
therapy (genetic immune modulation); (4) Antiangiogenic gene therapy; and (5) Oncolytic virotherapy.
(1) Suicide gene therapy:
It is the most commonly used technique in clinical
trials for brain tumors. It inv olves transducing tumor
cells with a gene encoding an enzyme that can
metabolize a nontoxic pro-drug to its toxic form (AsadiMoghaddam and Chiocca, 2009).
Herpes simplex virus type-1 thymidine kinase/
ganciclovir: in this approach, the t umor cells are
transduced to express herpes simplex virus thymidine
kinase using retroviral or adenoviral vector and treated
with the antiviral agent ganciclovir. Herpes simplex
virus thymidine kinase is an enzyme that metabolizes
nontoxic drugs such as ganciclovir, acyclovir, or
valacyclovir, into a cytotoxic metabolite. The ganciclovir
metabolite is incorporated into DNA, causing DNA
elongation to terminate and subsequently cause cell death
(Chen
et
al.,
1994).
Preclinical
experiments
demonstrated marked tumor elimination, despite gene
transfer into only a small fraction of tumor cells. This
was due to the cytotoxic effect of the transduced cells on
the adjacent non-transduced cells which is called the
bystander effect. Furthermore, the tumor cells treated
with this approach displayed enhanced sensitivity to
radiation in culture and in vivo (Asadi-Moghaddam and
Chiocca, 2009).
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Chapter 8
Gene & Viral Therapies
Cytosine
deaminase/5-Fluorocytosine:
in
this
approach, the tumor cells are transduced to express
cytosine deaminase and treated with the antifungal agent
5-Fluorocytosine. 5-Fluorocytosine is a pro-drug
converted into cytotoxic active agent 5-fluorouracil by
cytosine deaminase. 5-Fluorocytosine is nontoxic to
human cells because of the lack of cytosine deaminase.
The toxic effects of 5-fluorouracil are mediated by its
intracellular metabolites, which cause DNA strand
breakage leading to cell death (Aghi et al., 1998). Two
preclinical studies for glioblastoma using an adenoviral
vector
carrying
the
cytosine
deaminase
gene
demonstrated promising results (Asadi-Moghaddam and
Chiocca, 2009).
Cytochrome P450/cyclophosphamide: as in previous
approaches, cyclophosphamide is a pro-drug that is
activated by liver-specific enzymes of the cytochrome
P450 family. The active form of cyclophosphamide
(phosphoramide mustard) is an alkylating agent that
generates DNA cross links and consecutive DNA strand
breaks. The efficacy of cyclophosphamide in treating
brain tumors has been limited by the fact that its active
metabolites are poorly transported across the blood -brain
barrier (Wei et al., 1994).
Replacement of parts of the herpes simplex virus
type-1 genome with the cytochrome P450 gene has led to
the design of a herpes simplex virus type-1 vector that
can kill tumor cells through three modes: 1) using viral
oncolysis, 2) making the infected cell sensitive to
cyclophosphamide, and 3) making the infected cell
sensitive to ganciclovir. Animal studies of glioma cell
lines showed tumor regression when the animals were
treated with this modification (Asadi-Moghaddam and
Chiocca, 2009).
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Chapter 8
Gene & Viral Therapies
(2) Tumor suppressor gene therapy:
This includes transfer of tumor suppressor genes and
cell-cycle modulators. The p53 tumor suppressor protein
regulates cell-cycle progression and apoptosis in
response to many external insults (e.g., DNA damage and
oncogenic mutations) (Vousden K and Lane, 2007).
Mutations in the p53 gene resulting in loss of its
function are common in astrocytomas, and are associated
with tumor progression from low-grade astrocytoma to
glioblastoma (Louis et al., 2001). Accordingly, the p53
gene became an attractive candidate for gene transfer in
an attempt to restore cell cycle regulation in p53-mutated
cells and induce apoptosis, even in tumors with intact
functional genes, by causing enhanced expression of the
gene product (Roth, 2006).
Another commonly affected cell -cycle pathway in
gliomas is the retinoblastoma protein/cyclin -dependent
kinases/cyclin-dependent
kinase
inhibitors
circuit.
Preliminary studies restoring the genomic region of these
defects in glioblastoma cell lines demonstrated tumor
growth arrest or apoptosis. Another candidate for a gene
therapy approach is the epidermal growth factor receptor
gene, which shows frequent amplification in primary
glioblastomas (Asadi-Moghaddam and Chiocca, 2009).
Transfer of several pro-apoptotic genes, such as
factor-related apoptosis-inducing ligand has shown
promising pre-clinical results in vitro and in vivo studies.
Transfer of caspase-8 was showed to augment apoptosis
in vitro on human malignant glioma cells (Germano and
Binello, 2009).
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Chapter 8
Gene & Viral Therapies
(3) Immunogene therapy:
Gene therapy approaches aiming at genetic immune
modulation enhance the immune response against tumors
by expressing cytokines and lymphokines. The frequently
used cytokines to achieve genetic immune modulation
are
interleukin-2,
interleukin-4,
interleukin-12,
interferon β, interferon γ, and granulocyte-macrophage
colony stimulating factor. Several studies have been
performed by infecting tumor cells ex vivo (outside the
patient) with cytokine genes. Another model introduces
immune modulating genes into the tumor so infection
occurs in situ. Several phase I trials are currently
underway using this strategy. However, for interleukin-2
and interferon γ severe CNS toxicity has been reported
when these cytokines were secreted by tumor cells
intracranially (Asadi-Moghaddam and Chiocca, 2009).
In a recent clinical trial in humans with recurrent
gliomas, an adenoviral vector was employed to deliver
the gene for human interferon β and this resulted in
increased apoptosis in tumors (Chiocca et al., 2008).
Gene therapy can also be used to generate tumor
vaccines by inducing tumor antigen presentation by
antigen presenting cells (Asadi-Moghaddam and
Chiocca, 2009).
(4) Anti-angiogenic gene therapy:
Neovascularization is a feature of malignant gliomas
and is dependent on several potent angiogenic factors
secreted by tumor cells. Vascular endothelial growth
factor is an important overexpressed angiogenic factor in
gliomas. It has been shown that in vivo transfer of a n
adenoviral vector carrying gene for vascular endothelial
growth factor in an antisense form inhibits glioma
growth. Antisense form means single strands of DNA or
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Chapter 8
Gene & Viral Therapies
RNA that can bind to a complementary RNA sequence
preventing protein synthesis (i.e. preventing vascular
endothelial growth factor synthesis) (Asadi-Moghaddam
and Chiocca, 2009).
Other strategies are directed at the vascular
endothelial growth factor receptors. A mutant vascular
endothelial growth factor receptor was transferred into
xenografted glioma using retroviral vector. Histological
analysis revealed reduced vascular density, decreased
tumor cell proliferation and increased apoptosis and
necrosis (Benítez et al., 2008).
(5) Oncolytic Virotherapy:
Oncolytic viruses are engineered to selectively
replicate in cancer cells killing these cells without
affecting healthy cells. The virus replicates in the cancer
cell then thousands of new viruses are released and
infect neighboring cancer cells (Fig. 14). The cycle
continues until tumor cells are completely eradicated
(Benítez et al., 2008).
These viruses are capable of selectively lysing tumor
or dividing cells, making their use potentially safe in the
brain where most cells are not-dividing (Germano and
Binello, 2009).
Oncolytic Adenovirus:
Oncolytic adenoviruses are engineered or naturally
occurring strains of virus that replicate better in tumor
cells versus normal cells (Asadi-Moghaddam and
Chiocca, 2009).
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Chapter 8
Gene & Viral Therapies
Oncolytic Virus
Fig . 1 4 . Gener al mechanism o f
Mo g ha d d a m a nd Chio cca , 2 0 0 9 ) .
o nco lytic
virus
selectivity (Asa d i -
Herpes Simplex Virus Type-1:
Herpes simplex virus type-1 as an oncolytic virus
offers several advantages: 1) the ability to incorporate
large load of foreign DNA; 2) the ability to infect human
cells with high efficiency; 3) the sensitivity to the antiherpetic agents, such as ganciclovir providing a safety
mechanism by which virus replication can be eliminated
when needed; and 4) herpes simplex virus type-1 never
integrates into the host genome so the risk of insertional
mutagenesis is absent. The disadvantage of herpes
simplex virus type-1 is that its genetic manipulation is
more difficult than that of adenoviruses due to the large
size of the viral genome (Asadi-Moghaddam and
Chiocca, 2009).
Newcastle Disease Virus (NDV):
A phase I/II trial of intravenous infusion of an
oncolytic Newcastle disease virus in glioblastoma
patients reported that good tolerance to the virus was
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Chapter 8
Gene & Viral Therapies
observed, but only one patient achieved a complete
response (Freeman et al., 2006).
Reovirus:
Reovirus can replicate to very high levels in an
infected cell, and thus it could provide a good
therapeutic effect because the large number of virus
could infect a large number of neighboring tumor cells.
One of the issues that limit use of this virus relates to its
small size which makes genetic manipulation difficult
(Asadi-Moghaddam and Chiocca, 2009).
Gene Therapy Trials:
Six viruses; two replication-incompetent (retrovirus
and
adenovirus)
and
four
replication-competent
(adenovirus, herpes simplex virus type-1, Newcastle
disease virus and reovirus) have been studied in clinical
brain tumor trials in which the results have been
published. Measles virus has been studied in glioma
patients in a trial that is still ongoing and whose results
have yet to be published (Asadi-Moghaddam and
Chiocca, 2009).
Retrovirus and adenovirus have been genetically
modified to express herpes simplex virus thymidine
kinase with concurrent ganciclovir administration. The
first study using gene therapy in glioma patients used
stereotactic intratumoral inoculation of a retroviral
vector carrying herpes simplex virus thymidine kinase
gene in 15 patients with recurrent malignant brain tumor.
Although this study showed some promising results in
terms of antitumor efficacy, it was not a controlled or
randomized protocol (Ram et al., 1997).
Two subsequent phase I and II studies in patients with
recurrent glioblastoma were performed using a herpes
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Chapter 8
Gene & Viral Therapies
simplex virus thymidine kinase followed by ganciclovir
administration. The first study involved 12 patients and
no treatment-related adverse effects were noted. The
overall median survival was 6.8 months, with three
patients surviving > 12 months and one patient was
recurrence-free 2.8 years after treatment (Klatzmann et
al., 1998).
A comparable international, multicenter study used
herpes simplex virus thymidine kinase with concurrent
ganciclovir administration in 48 patients with recurrent
gliomas. The median survival time was 8.6 months, with
a 12-month survival rate of 27%. Tumor recurrence was
absent on MRI in seven patients for at least 6 months and
in two patients for 12 months, and one patient remained
recurrence-free at 24 months (Shand et al., 1999).
A similar phase I study was performed in 12 children
(aged 2 to 15 years) with recurrent malignant
supratentorial tumors. This study also used the previous
approach. Disease progression occurred at a median time
of 3 months after treatment, and the longest time until
progression was 24 months with no adverse effects were
noted (Packer et al., 2000).
A large controlled phase III trial seemed necessary
for confirmation of the efficacy of the retroviral herpes
simplex virus thymidine kinase with ganciclovir
administration approach. This study used an adjuvant
gene therapy protocol to the standard therapy of
maximum surgical resection and irradiation for newly
diagnosed glioblastoma. After 4 years of follow-up of
248 patients, survival analysis showed no advantage of
gene therapy in terms of tumor progression and overall
survival (Rainov, 2000).
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Chapter 8
Gene & Viral Therapies
A phase I/II trial evaluated an adenoviral vector
expressing the herpes simplex virus thymidine kinase
with ganciclovir administration gene in patients with
primary or recurrent high-grade gliomas. This study was
performed in a controlled randomized fashion on 36
patients (i.e., 17 in the treatment arm and 19 in the
control group). The treatment group underwent surgical
resection and adenoviral injection, followed by
intravenous ganciclovir on postoperative day 5 for 14
days. The control group underwent resection only. The
median survival in the gene therapy group was
significantly longer than the control group (62 vs. 37
weeks) (Immonen et al., 2004).
An adenoviral vector delivering a wild-type copy of
the p53 transgene was also evaluated in humans with
recurrent gliomas. The vector was initially introduced by
an implanted catheter placed in the middle of the tumor
bed, followed by resection of the tumor to allow for
studies related to p53 gene delivery and distribution.
Again, while the treatment was well tolerated, the
distribution of p53 gene into tumor was relatively low
(Lang et al., 2003).
One recent trial evaluated an adenoviral vector in 11
patients with recurrent high -grade glioma introduced by
stereotactic injection, followed by surgical resection and
an additional injection of the ve ctor into the tumor bed.
The vector was well-tolerated in all patients. One patient
experienced confusion after the postoperative injection,
which was believed to be caused by local brain toxicity.
Tumor resection after the viral treatment showed a
biologic effect from the transferred gene (Chiocca et al.,
2008).
A phase I trial evaluated the safety of an oncolytic
herpes simplex virus type-1 in 9 patients with recurrent
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Chapter 8
Gene & Viral Therapies
glioblastoma.
Direct
intratumoral
injection
was
performed with no adverse clinical symptoms or
induction of encephalitis, nor reactivation of latent
herpes simplex virus, thus appearing as if tumor
progression was controlled with some efficacy
(Rampling et al., 2000).
Another clinical trial using a different herpes simplex
virus type-1 mutant included 21 patients with recurrent
glioma with similar results as they relate to safety
(Markert et al., 2000).
Strategies to decrease the immune response prior to
administration of virus have also provided strong preclinical data. The therapeutic ef fects of the oncolytic
herpes simplex virus can be enhanced by coadministration of cyclophosphamide, which decreases
production of gamma-interferon and results in additional
spreading of the virus (Fulci et al., 2006).
A large phase III trial in Europe u sing herpes simplex
virus type-1 is being conducted (Asadi-Moghaddam and
Chiocca, 2009).
Enhancing Gene Therapy:
Currently, two delivery methods to enhance gene
transfer have provided promising laboratory results: (1)
convection-enhanced delivery and (2) ultrasound. The
use of convection-enhanced delivery to homogenously
cover larger areas of the brain has been described in
laboratory studies and clinical trials for drug delivery. In
convection-enhanced delivery, programmable pumps and
specifically designed catheters are used. The hypothesis
that ultrasound can be used to enhance efficacy of
chemotherapeutics and intracellular gene delivery in
glioma cells in vitro was recently tested in gliosarcoma
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Gene & Viral Therapies
model. The findings suggest that ultrasound may be
useful to increase the efficacy of chemotherapy and gene
therapy (Germano and Binello, 2009).
Finally, the problem of delivering genetic vectors into
brain tumors and the efficient in situ gene transfer
remains one of the most significant difficulties in gene
therapy. The completed brain tumor gene therapy trials
have offered some promising results. However, the
results of most clinical studies have not lived up to the
expectations created by experimental data. Although
gene delivery to human patients seems to be safe, these
studies have not yet translated into benefits in the clinic.
At present, gene therapy is being studied in trials for
brain tumors, and so far it is not available outside of a
clinical trial (Asadi-Moghaddam and Chiocca, 2009).
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Discussion
Discussion
Discussion
It is thought that maximal surgical resection of
gliomas,
the
commonest
primary
brain
tumor,
significantly improves survival but there is no good
evidence from randomized trials that resection offers any
survival advantage (Metcalfe and Grant, 2001).
Collected data on symptoms before and after surgical
resection of brain tumors report that 32% had an
improvement in their symptoms, 58 –76% were not
different, and 9–26% had a worsening. Neurosurgery can
improve some symptoms, but it can also c reate new ones ,
it can be associated with local or systemic complications
(Hart and Grant, 2007).
Despite advances in radiotherapy and chemotherapy
along with surgical resection, the prognosis of patients
with malignant brain tumors is poor. Therefore, the
development of new treatment modalities is extremely
important. Most brain tumor patients usually undergo
multimodality treatments after histological diagnosis
(Yamanaka and Itoh, 2007).
There are many controversies surrounding current
non-surgical therapies. Drug delivery across the bloodbrain barrier is one of the vital problems, so the dilemma
now is what is the most efficient way to deliver drugs to
the brain (Sawyers, 2006)? Also, it is difficult for the
drugs to reach the intraparenchymal regions in the brain
beyond the resection cavity. This becomes a burden with
micrometastases and infiltrative satellites that are
commonly seen in glioma. Therefore, researchers
developed convection-enhanced delivery as a novel way
to deliver drugs across blood-brain barrier as well as
- 147 -
Discussion
over a large volume of tissue. This method has become
especially relevant in brain tumors as it bypasses bloodbrain barrier and reduces systemic toxicities (Mercer et
al., 2009).
There are several non-surgical treatment modalities
for brain tumors starting with radiation therapy and
chemotherapy that represent the backbone of the non surgical
treatment,
till
immunotherapy
and
antiangiogenic therapy that showed promising clinical
results, and finally gene and viral therapies that hold
promise in the near future. Also, we can not forget the
endocrinal therapy that showed great success in the field
of management of pituitary adenomas.
Radiation therapy plays a primary role in the
management of most malignant and many benign brain
tumors. It is used frequently postoperatively as (Stieber
and Mehta, 2007):
(a) Adjunctive therapy: to 1) decrease local failure, 2)
delay tumor progression, and 3) prolong survival (as
in malignant gliomas).
(b) Curative treatment for diseases such as primitiv e
neuroectodermal tumors and germ cell tumors .
(c) Therapy that stops further tumor growth as in
schwannoma, meningioma, pituitary tumors, and
craniopharyngioma.
Survival benefit for postoperative whole brain
radiation therapy for glioma was demonstrated in studies
going back three decades ago. Median survival increased
from 17 weeks in patients treated with conventional
measures to 37.5 weeks in patients treated with
postoperative whole brain radiation therapy (Norden and
Wen, 2006).
- 148 -
Discussion
Subsequent advances in radiotherapy techniques have
used advanced imaging of the tumor and focused on
radiotherapy techniques that maximize treatment to the
tumor while minimizing radiation to normal b rain tissue.
Focal radiotherapy, termed involved field radiotherapy
has replaced whole brain radiation therapy as the
standard approach. Some types of involved field
radiotherapy
include
3
dimensional
conformal
radiotherapy and intensity modulated radiotherapy that
provides particular advantages when the target is
critically close to the radiation-sensitive structures, as
the dose to these structures can be minimized without
affecting the dose to the tumor that needs to be treated
(Omay and Vogelbaum, 2009).
Radiotherapy has side effects that include local scalp
irritation, hair loss, somnolence and fatigue in the short
term. Late side effects include radiation leucoencephalopathy (comprising of dementia, incontinence
and gait disturbance). Its effectiveness, ease of
administration and acceptable short -term side effects
profile make it a standard treatment for the most of
malignant brain tumors (Hart and Grant, 2007).
Because the majority of malignant gliomas recur in
close proximity to the original tumor and multifocal or
disseminated disease is uncommon, there is great interest
in maximizing the radiation dose to the tumor bed
without increasing radiation exposure to the surrounding
brain tissue. Stereotactic radiosurgery offer this
advantage. It can deliver a high accurate single dose of
radiation (Omay and Vogelbaum, 2009).
Stereotactic radiosurgery with a Gamma Knife or
CyperKnife is now being used as (A) primary
management or (B) booster treatment with whole brain
radiation therapy, in brain metastasis (Yamamoto, 2007).
- 149 -
Discussion
Controversy persists as to whether stereotactic
radiosurgery should be combined with whole brain
radiation therapy? Although some reports have supported
combining stereotactic radiosurgery with whole brain
radiation therapy to achieve optimal tumor control and
survival periods (Chidel et al., 2000), others have
questioned usefulness of whole brain radiation therapy
(Sneed et al., 2002). Neither the survival rate nor the
local tumor recurrence rate differs significantly between
groups with vs without whole brain radiation therapy
(Yamamoto, 2007).
Although the size limitation on treatable lesions
(should be < 4 cm) is crucial in stereotactic radiosurgery,
tumor control rates of 90% can be expected if 1-4 lesions
are irradiated with a peripheral dose of 20 Gy or more. In
such cases, true recurrence is extremely rare. Postradiosurgical MRI reveals disappearance of the tumors
and complete cure (Pollock and Brown, 2002).
Gamma Knife radiosurgery is superior to whole brain
radiation therapy for several reasons: (1) a brief hospital
stay, (2) Higher control rates and earlier symptom
palliation, (3) All observable lesions on MRI can be
treated, (4) Other treatments, such as surgery and
chemotherapy, need not be interrupted, (5) Availability
of an alternative treatment allows whole brain radiation
therapy to be reserved for subsequent treatment attempts
when it become absolutely necessary, (6) Radiosurgery
can be repeated, even after whole brain radiation therapy
which usually cannot be repeated, (7) Patients never lose
all of their hair, (8) A very low incidence of dement ia
can be expected, (9) Radiosurgery can be used as
postoperative irradiation instead of whole brain radiation
therapy that has several disadvantages (Yamamoto,
2007).
- 150 -
Discussion
Stereotactic radiosurgery may represent also an
alternative or supplementary modality t o conventional
surgery in small-volume low-grade astrocytomas. There
is also evidence for beneficial effect of stereotactic
radiosurgery on the survival of patients with high-grade
gliomas (Szeifert et al., 2007). Future studies are needed
to identify patients most likely to respond to stereotactic
radiosurgery (Biswas et al., 2009).
Multiple studies demonstrated the efficacy and safety
of stereotactic radiosurgery in treatment of meningioma,
with tumor control rates ranging from 60 to 100%
depending on the proportion of atypical or malignant
meningiomas (Lee et al., 2002). Given the benefit of
radiosurgery, stereotactic radiosurgery is increasingly
used to treat patients as a primary therapy based on
imaging criteria only (Flickinger et al., 2003).
Radiosurgery is considered as an effective management
choice for patients with small to medium-sized
symptomatic, newly diagnosed or recurrent meningiomas
of the brain (Kondziolka et al., 2008).
Stereotactic radiosurgery is also safe and highly
effective treatment for patients with pituitary adenomas.
Radiosurgery provides control of tumor growth in nearly
all cases and hormone normalization in the majority of
secretory tumors (Mayberg and Vermeulen, 2007).
Although, stereotactic radiosurgery is not a risk-free
treatment and some patients may develop complications.
Complications of stereotactic radiosurgery that have
been reported include acute coronary events, severe pain,
headaches, facial pain, new motor deficits, symptomatic
hydrocephalus and delayed seizures (Vachhrajani et al.,
2008).
- 151 -
Discussion
Chemotherapy has played primarily an adjuvant role
because of efficacy limitations related to the nonspecific nature of chemotherapeutic agents, drug delivery
issues, and inherent tumor chemoresistance (Cairncross
et al., 1998). There is now clear evidence that
chemotherapy can improve survival. Debates have
continued over whether this increase in survival is
clinically significant. Further trials need to consider the
quality of life as well as survival benefit (Hart and
Grant, 2007).
The most commonly used drugs were nitrosoureas,
either alone or in combination with other agents (Walker
et al., 1980).
Temozolomide is now the preferred agent for
concurrent and adjuvant chemotherapy in patients with
gliomas (Batchelor and Supko, 2008). More recent
evidence
supports
temozolomide
effect
as
a
radiosensitizer also (Van Nifterik et al., 2007).
Temozolomide
was
associated
with
significant
improvements in median survival, progression-free
survival, overall survival, and two -year survival. This
improvement in survival was achieved with no harmful
effect on the quality of life of the patients (Batchelor
and Supko, 2008).
Concomitant chemo-radiotherapy followed by singleagent adjuvant treatment with the temozolomide was
associated with a significant improvement in median
survival and also it was well tolerated in all patients
(Stupp et al., 2005). It is the current standard of care for
glioma patients. Concomitant chemo-radiotherapy as
well as the early introduction of chemotherapy, appears
to be the key to improving outcome (Stupp et al., 2007).
- 152 -
Discussion
Efforts to maximize efficacy of chemotherapy by
overcoming the blood-brain barrier limitations included:
(1) intra-arterial delivery, (2) disruption of the bloodbrain barrier and (3) implantation of the drug directly in
the tumor bed. Dose intensification intended to increase
drug gradients across the blood-brain barrier for
improved penetration is often faced by added systemic
toxicity (Ashby et al., 2001).
Trials of molecularly targeted drugs as monotherapy
for gliomas were disappointing, with some potential
benefit when used in combination with nitrosurea or
temozolomide. Combinations of multitargeted therapies
are currently the focus of clinical trials (Kreisl, 2009).
Two
aspects
are noteworthy in regard
to
chemotherapeutic
molecular
agents.
Pretreatment
molecular profiling of tumors will be increasingly
needed to determine if the mechanism of a drug is
appropriate to the genetic alterations found within
individual tumors. In addition to traditional clinical
endpoints, biological end-points (change in serum tumor
markers, measures of target inhibition) seem to be
appropriate, and in particular dosing schedules in phase I
trials that focus on the determination of an optimal
biological dose rather than the maximum tolerated dose
must be explored. Finally, multitargeted agents are
needed to target simultaneously multiple signaling
pathways that concur at the same time or sequentially, as
a compensatory activation, to tumor growth and
resistance to treatments (Soffietti et al., 2007).
Better understanding of the molecular pathogenesis of
brain tumors will allow development of specifically
targeted therapies. Correlative molecular studies, now
included in most ongoing trials, will enhance our
- 153 -
Discussion
understanding of this disease and allow for rapid further
improvement in outcome (Stupp et al., 2007).
Immunotherapy gives the promise of targeting the
tumor cells for destruction with an excellent specificity
and efficiency, while at the same time completely sparing
the
normal
cells
(Mitchell
et
al.,
2008).
Immunotherapeutic approaches include: 1) passive
immunotherapy, 2) active immunotherapy (tumor
vaccines), and 3) adoptive immunotherapy (largely
abandoned nowadays) (Omay and Vogelbaum, 2009).
Passive immunotherapy using the anti-vascular
endothelial growth factor monoclonal antibodies
bevacizumab (Avastins®) showed good results specially
the combination of bevacizumab and chemotherapy that
have shown promising response rates and evidence of
prolongation of survival in recurrent glioblastoma
patients (Vredenburgh et al., 2007).
Active immunotherapy or a successful vaccine for
brain tumors has been a ‘holy grail’ in neuro-oncology
(Ebben et al., 2009). Peptide-based vaccines represent a
major focus of cancer vaccine research (Yamanaka and
Itoh, 2007). Dendritic cell-based vaccines has also
shown potential efficacy as a method of overcoming
chemotherapy resistance (Liu et al., 2006). There are
several promising vaccines under investigation in
different phases including: (1) CDX-110, (2) DCVax, (3)
Oncophage, (4) Poly-ICLC (Das et al., 2008).
Immunotherapy did not emerge as a single-modality
treatment for brain tumors, but it may take its place as a
very effective adjuvant therapy. Dendritic cell and
peptide-based therapies appear promising as an approach
to successfully induce antitumor immune response and
prolong survival. They seem to be safe and without
- 154 -
Discussion
major side effects. Their efficacy should be studied in
randomized controlled clinical trials (Yamanaka, 2009).
However, a number of limitations still exist on the
clinical efficacy of immunotherapy with antibodies. The
main unresolved problem stems from the question
whether treatments administered systemically can
achieve clinically significant levels at the site of
intracranial tumors. Sufficient levels may not be
achieved with the dosage and systemic route of
administration. Clinical attempts to ‘open up’ the Bloodbrain barrier to drug delivery have met with both failure
and toxicity. Other problems that remain for systemic
delivery are the high interstitial pressures in the tumor
and surrounding tissue which prevent perfusion. In
addition, the use of antibodies introduces a problem that
is the antibodies themselves are antigenic. The
development of human anti-human antibodies against the
therapeutic antibodies is not infrequent event (Mitchell
et al., 2008).
Currently,
anti-angiogenic
therapy
is
being
increasingly adopted for treating glioblastoma (Argyriou
et al., 2009). Because of vascular endothelial growth
factor prominent role in glioma angiogenesis, its
pathway was rapidly identified as an attractive
therapeutic target (Chi et al., 2009).
Bevacizumab (Avastin®), as mentioned before, is an
anti-vascular endothelial growth factor monoclonal
antibodies but also has strong anti-angiogenic effect.
Bevacizumab showed promising radiographic response
proportions in recurrent glioblastoma and in recurrent
anaplastic glioma. Responses were also associated with
neurological
improvement
and
reduction
or
discontinuation of corticosteroid requirements (Wagner
et al., 2008). Additionally, several retrospective studies
- 155 -
Discussion
have reported similar findings with bevacizumab.
Radiographic response proportions between 35% and
50% were observed with combination of bevacizumab
and conventional chemotherapy (Guiu et al., 2008).
Cediranib which is a potent pan-vascular endothelial
growth factor receptor inhibitor with modest activity
against platelet derived growth factor receptor showed
radiographic response in 56% of patients and there was a
modest improvement in median overall survival.
Furthermore, an antiedema effect was detected
(Batchelor et al., 2008).
Other anti-angiogenic drugs include epidermal growth
factor receptor inhibitors such as cetuximab, gefitinib
and erlotinib. A phase I/II study investigating the
efficacy and safety of cetuximab plus concomitant
chemoradiotherapy is currently ongoing. Monotherapy
with gefitinib is not superior in terms of efficacy over
conventional chemotherapy. Overall, therapy with
erlotinib or gefitinib is associated with modest
therapeutic efficacy (Argyriou et al., 2009). The newer
platelet derived growth factor receptor inhibitors,
tandutinib and dasatanib, have potentially greater
efficacy in malignant gliomas due to improved CNS
penetration, and they are in clinical trials for recurrent
gliomas (Chi et al., 2009).
A number of issues remain unresolved concerning the
anti-angiogenic therapy, including: 1) toxicity profiles,
2) radiographic assessment, 3) biomarkers, and 4)
resistance. A definite survival advantage has yet to be
established but current evidence suggests that antiangiogenic therapy has clinical benefits including
steroid-sparing effect and increased progression-free
survival (Chi et al., 2009).
- 156 -
Discussion
Toxicity profiles of anti-angiogenic therapy include
risks of hemorrhage and thrombosis that have been
ongoing concerns with the use of anti-angiogenic drugs.
Epistaxis is not infrequent. The intracranial hemorrhage
risk appears to be low, and events are often
asymptomatic (Norden et al., 2008). Common toxicities
include fatigue and hypertension. Impaired wound
healing is also observed (Lai et al., 2008). Other
toxicities include proteinuria, skin toxicity, diarrhea and
mucositis. Other rare but serious complications include
myocardial
infarction,
stroke,
posterior
leukoencephalopathy, and thrombotic thrombocytopenic
purpura (Chi et al., 2009).
Standard criteria of response to anti-angiogenic
therapy, currently in use, are dependent on contrastenhancement on CT or MRI (Macdonald et al., 1990).
Obtaining accurate assessment of response is problematic
in brain tumor patients (Sorensen et al., 2008).
Clinical data suggest that benefits gained from anti angiogenic agents will be short-lived. One of the major
problems is that almost all patients treated with antiangiogenic therapy progress during treatment, as tumors
finally acquire resistance (Quant et al., 2009).
Currently available treatments for brain tumors
necessitate the development of more effective tumor selective therapies. The use of gene therapy for brain
tumors is promising as it can be delivered in situ and
selectively targets the tumor cells while sparing the
adjacent normal tissue (Germano and Binello, 2009).
Five gene therapy approaches are currently being
explored: (1) Suicide gene therapy; (2) Tumor suppressor
gene therapy; (3) Immunogene therapy; (4) Antiangiogenic gene therapy; and (5) Oncolytic virotherapy
(Asadi-Moghaddam and Chiocca, 2009).
- 157 -
Discussion
Suicide gene therapy is the most commonly used
technique. Preclinical studies showed marked tumor
elimination. Furthermore, the tumor cells treated with
herpes simplex virus thymidine kinase with ganciclovir
administration displayed enhanced sensitivity to
radiation. A phase I/II trial evaluated this approach in
glioma patients. The median survival in the gene therapy
group was significantly longer than the control group (62
vs. 37 weeks) (Asadi-Moghaddam and Chiocca, 2009).
At present, gene therapy is being studied in trials for
brain tumors, and so far it is not available outside of
these clinical trials (Asadi-Moghaddam and Chiocca,
2009). Finally, gene therapy has not yet been an
effective tool in the treatment of gliomas. It offers new
ways to attack these tumors and when used together with
surgery, chemotherapy and radiation therapy, it will be a
valuable adjuvant therapy to improve survival and the
quality of life of the patients (Benítez et al., 2008).
Problem of the delivery of genetic vectors into solid
brain tumors and efficient in situ gene transfer remains
one of the most significant hurdles in gene therapy. The
efficiency of transduction could be improved . The
currently used manual injection of vectors might be
improved
by
the
use
of
three-dimensional
neuronavigation techniques and convection-enhanced
delivery methods (Asadi-Moghaddam and Chiocca,
2009).
The disadvantages of gene therapy include low
tumoricidal effect and a limited distribution of the
transgenes (transferred genes) and/or the vectors to
tumor cells, making treatment localized peripherally
from the main tumor mass. In addition virus-derived
vectors may have the potential to create damaging
immunological reactions by immune -mediated toxicity,
- 158 -
Discussion
especially in the presence of circulating antibodies to the
virus vectors or by triggering immune reactions to self or
transgene antigens (Omay and Vogelbaum, 2009).
The medical approach to pituitary adenomas greatly
improved since availability of dopamine agonists such
as: bromocriptine, cabergoline and quinagolide, and
availability of somatostatin analogues such as:
lanreotide and octreotide (Colao et al., 2009).
Bromocriptine is successful in 80–90% of patients
with microprolactinomas in normalizing serum prolactin
level, restoring gonadal function and shrinking tumor
mass. For macroprolactinomas, normalization of serum
prolactin level and tumor mass shrinkage occur in about
70% of patients. Cabergoline also is widely used to treat
prolactinomas. The tumor shrinking effect of cabergoline
is very rapid and improvement of visual field defects can
be detected even after the administr ation of the first
tablet. Cabergoline is superior over bromocriptine and
can be given to patients previously intolerant or resistant
to bromocriptine (Colao et al., 2009).
For growth hormone secreting adenomas, dopamine
agonists are primarily effective only in tumors that cosecrete prolactin or that exhibit immunostaining for
prolactin (Melmed et al., 2002). Somatostatin analogues
appear to be more effective. They showed reduction in
tumor size in 45% of patients (Bevan, 2005).
Combination treatment with dopamine agonists and
somatostatin analogues could be beneficial to better
suppress growth hormone level and also on tumor
shrinkage. The effect of somatostatin analogues on
tumor shrinkage is reversible as demonstrated by tumor
re-growth after stopping somatostatin analogues (Colao
et al., 2009).
- 159 -
Discussion
For thyroid stimulating hormone secreting adenomas,
treatment depends mainly on the administration of
somatostatin analogues, as dopamine agonists failed to
persistently block thyroid stimulating hormone secretion
in almost all patients and caused tumor shrinkage only in
tumors that co-secrete prolactin (Kienitz et al., 2007).
A potential disadvantage of medical therapy for
pituitary adenomas in general is that it requires life-long
daily or weekly treatment. He nce, issues about
compliance and cost become important, especially for
younger patients. Somatostatin analogues are costly, and
long-term use of these drugs makes this a significant
issue. Common but often transient side effects of
somatostatin analogues include nausea, abdominal
discomfort and diarrhea. Furthermore, somatostatin
analogues inhibit the secretion of insulin and glucagon
and cause cholelithiasis in up to 20% of patients (Patil et
al., 2009).
Side effects of bromocriptine include nausea,
dizziness (orthostatic hypotension), nasal stuffiness,
difficulty concentrating, depression, psychosis, and
peripheral vasospasm. These side effects can be
minimized by a slow increase in medication dosage and
initiation of therapy at night. A rare side effect of
bromocriptine is delayed reversible visual loss. Side
effects with cabergoline are similar, but appear to be less
common and less severe than bromocriptin e . A recent
study has suggested that cabergoline administration may
be associated with cardiac valve insufficiency in patients
with Parkinson’s disease (Patil et al., 2009).
Corticosteroids are an established treatment for
symptomatic relief from brain edema and usually
indicated
in
any
patient
with
brain
tumor.
Dexamethasone is used most commonly as it has little
- 160 -
Discussion
mineralocorticoid activity and, possibly, a lower risk for
infection and cognitive impairment compared with other
corticosteroids (Batchelor and De Angelis, 1996).
Dexamethasone produces symptomatic improvement
within 24 to 72 hours. The usual starting dose is a 10 mg
load, followed by 16 mg per day in patients who have
significant symptomatic edema (Drappatz et al., 2007).
There is a lack of randomized controlled trials to prove
their effectiveness. Care needs to be taken when
withdrawing steroids. Side effects are common and can
be significant (Hart and Grant, 2007).
The side effects of corticosteroids are the driving
force to search for alternative therapies for cerebral
edema.
Corticotropin-releasing
factor
reduces
peritumoral edema by a direct effect on blood vessels.
Inhibitors of vascular endothelial growth factor or inhibitors
of its receptors reduce the tumor-related edema and they
are more effective and less toxic alternatives (Drappatz
et al., 2007).
Although the progress in understanding of the biology
of brain tumors has improved, survival rates are
improving only marginally. The heterogeneity of genetic
and biochemical alterations and the invasive nature of
malignant brain tumors especially gliomas, make the
future treatment strategies for these neoplasms are likely
to consist of a combination of agents or strategies that
will act synergistically at different levels to stop tumor
growth. Surgery and radiotherapy have not lost their
importance and a recent advance in the use of conc urrent
chemo-radiation has improved survival in a large
fraction of patients. A variety of new treatment
modalities are undergoing development and are studied
in various clinical trials. These new treatment modalities
hold promise for further survival gains and improvement
in the quality of life of the patients in the near future.
- 161 -
Discussion
Trials in this area need to be larger and randomized, with
greater attention to symptom profile and quality of life in
their outcome analysis.
There is no magic bullet for malignant brain tumors
in the foreseeable future, and clinical improvements will
likely be because of the synergistic effects of a
multitargeted attack. Although preclinical data are
promising, clinical trials have been delayed by ethical
concerns, and all of the treatment strategies are still
searching for a significant survival benefit in phase II or
III clinical trials. These strategies have their own distinct
advantages and limitations.
- 162 -
Summary
Summary
Summary
Despite advances in surgery, radiation, and
chemotherapy, the prognosis for patients with malignant
brain tumors has not markedly improved. Moreover, the
non-specific nature of the conventional therapies for
brain tumors often results in incapacitating damage to
surrounding normal brain and systemic tiss ues. There is
an urgent need for a search for new treatment modalities
that precisely target the tumor cells while minimizing
collateral damage to the neighboring brain tissue.
For more than 30 years, stereotactic radiosurgery has
provided patients with brain tumors an alternative focal
treatment to surgery. Initially, only benign tumors, such
as meningioma and acoustic neuroma, were selected for
treatment. In the last 15 years, radiosurgery as a
therapeutic option was also considered for patients with
brain metastases who had controlled systemic disease
and/or a good prognosis. Also we can use radiosurgery to
treat
small
tumor
residua
following
surgery.
Radiosurgery is a safe and effective therapy. It provides
local tumor control and prolongs survival.
Chemotherapy may be of value in selected patients,
increasing survival by 2–3 months, and the two regimes
that have been most widely used in the past were
lomustine, as a single agent, and procarbazine, lomustine
and vincristine as a combination regimen , more recently
temozolamide is being increasingly used. There is also
evidence that giving temozolamide in combination with
radiotherapy, and continuing the drug thereafter,
improves the survival by about 6 months, when compared
to radiation alone.
- 163 -
Summary
Concomitant chemo-radiotherapy followed by singleagent adjuvant treatment with the alkylating agent
temozolamide is the current standard of care for the
patients with gliomas. The concomitant chemoradiotherapy, as well as the early introduction of
chemotherapy, appears to be a key to the improving
outcome.
Recent developments in chemotherapy of brain
tumors include the combination of cytotoxic, cytostatic
and targeted therapies. Multitargeted compounds that
simultaneously affect multiple signaling pathways, such
as those involving epidermal growth factor receptors ,
platelet derived growth factor receptors and vascular
endothelial growth factor receptors , are needed and
increasingly employed.
Immunotherapy has emerged as a promising tool in
the management of brain tumors. Many novel
immunotherapeutic strategies are currently being
investigated in human trials, and have already been
found safe and efficacious in preliminary studies.
Dendritic cell and peptide-based strategies are promising
approaches. Their efficacy should be determined in large
randomized controlled clinical trials.
An effective vaccine would be a potent addition to
current therapeutic arsenal against brain cancers.
Significant progress has been made that offers new hope
and novel therapeutic opportunit ies. However, it is
important to realize that much additional work lies ahead
before an effective brain tumor vaccine is validated for
clinical use.
Current
evidence
suggests
that
angiogenesis
inhibitors have clinical utility for brain tumor patients.
Clinical benefits have manifested primarily as steroid
- 164 -
Summary
sparing effects and increased progression -free survival
but a definite survival advantage has yet to be
established with these drugs. Several issues and
obstacles remain in the clinical development of effective
anti-angiogenic agents for brain tumor patients.
Anti-angiogenic
drugs
such
as
bevacizumab,
cediranib, vandentanib, aflibercept, and cilengitide are
being evaluated in combination with standard therapy.
Other trials are evaluating combinations of antiangiogenic therapy with different cytotoxic agents or
targeted agents in attempts to improve upon the efficacy
gains already observed.
Tremendous progress has been made in the field of
gene therapy over the past decade and clinical trials are
beginning to show some clinical efficacy. As we learn
more about the biology of brain tumors and identify
efficacious genes to stop their growth, the clinical utility
of gene delivery strategies will become increasingly
evident.
Gene therapy offers new approaches to treat brain
tumors specially gliomas. However, the results from
clinical trials have not yet fulfilled the expectations
generated from very successful basic experiments. Gene
therapy offers new ways to attack these tumors and when
used together with surgical, chemotherapeutic and
radiation treatments will be a valuable adjuvant therapy
to improve survival and the quality of life of patients.
The management of pituitary tumors poses a unique
challenge that also requires a multimodality treatment
approach. This includes neurosurgical tumor resection,
medical therapy, radiotherapy and radiosurgery. Since
the late 1990s, several new medical therapies have
emerged. The efficacy of dopamine agonists in prolactin
- 165 -
Summary
secreting adenomas and efficacy of somatostatin
analogues in growth hormone and thyroid stimulating
hormone secreting adenomas is well established. More
recently, data are accumulating suggesting a potential
therapeutic role of dopamine agonists also in patients
with adrenocorticotrophic hormone secreting adenomas
and non-functioning pituitary adenomas .
A major cause of death in glioblastoma patients ( more
than 60% of cases) is brain herniation due to cerebral
edema, so corticosteroids are usually indicated in any
patient with brain tumor with symptomatic peri-tumoral
edema. The mechanism of action of corticosteroids is not
well understood. Corticosteroids reduce the tumorassociated edema in patients with brain metastases or
primary brain tumor as illustrated by CT studies . It
produces symptomatic improvement within 24 to 72
hours.
The prognosis for patients with malignant brain
tumors is poor. Conventional treatments such as surgery,
radiation therapy, and chemotherapy have done little to
affect long-term survival, and new methods of treatment
are urgently needed. The overall treatment of brain tumor
patients remains a challenge. Although mortality remains
a primary concern, morbidity and quality of life are
important issues.
- 166 -
Recommendations
Recommendations
Recommendations
Brain tumors are a group of heterogeneous neoplasms
that need multimodality treatments aiming at curing the
patients or at least increasing survival and at the same
time improving quality of life of those patients.
The available trials have provided results that have
challenged previously held beliefs and breathed new air
into treatment areas.
Based on the available data
recommendations for further
suggested:
the following
research are
(1) More experimental studies to clear the vague
points in the genetics and molecular pathogenesis
of brain tumors.
(2) More large randomized controlled double-blinded
trials for the different treatment modalities to
conclude specific treatment protocols.
(3) More trials interesting in improving quality of
life of the patients. Although survival is an
important endpoint, quality of life is as
important.
- 167 -
References
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Antiangiogenic agents in cancer therapy. 2nd ed, Humana
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399. Watanabe T, Nakamura M, Yonekawa Y, et al: Promoter
hypermethylation and homozygous deletion of the p14ARF
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400. Watanabe T, Yokoo H, Yokoo M, et al: Concurrent
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401. Weaver M, Laske DW: Transferrin receptor ligand -targeted
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402. Wei M, Tamiya T, Chase M, et al: Experimental tumor
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- 213 -
Arabic
Summary
‫الملخص العربي‬
‫الملخص العربي‬
‫أورام المق ق علق ق أي نم ققو شق ق بق ق ي خاليق ق أو أنسق ق‬
‫ُيطلق ق وصق ق‬
‫ال م م ق س قوا أك ن ق‬
‫تتوا ق ق ض ققم‬
‫أو ارم ق حمي ق ال تحتققوي عل ق خالي ق متسققرطن أو أو ارم ق خبيث ق‬
‫تتكو م خاليق سقرط ني أو أورام ن شقة بمواضق أخقر مق ال سقم وتنتشقر لتصقإ ىلق‬
‫الم وتسم أورام ً ث نوي ‪.‬‬
‫رغ ققم التط ققور الملح ققوج ا ققا الو ققالن ال ارح ققا وي ققإ مق ق الو ققالن ا ش ققو عا والو ققالن‬
‫الكيمق وي رورام المق‬
‫اققآ المققي المرضققا ليقاال المرضققا مق اا غيققر يق‬
‫اققا ح ق م سق ىلق وسق ةإ عال يق‬
‫متو‬
‫يق حيققر يحتق ن جقاال المرضق ىلق عال ق‬
‫للسيطر عل ج ه ارورام‪.‬‬
‫لقق يق ُيوتقق أ ىستةصق‬
‫بق جاال المرض عل قي الحي‬
‫ال ارس ق‬
‫الوش قواةي‬
‫صققوب المن ق‬
‫س قوا ي ق‬
‫أكبققر يققم مميق نسققيي الققورم ُيحسق بشققيإ ملحققوج اتققر‬
‫ولكق ال يو ق أي ليقإ ققوي يثبق‬
‫يم ق أ ا ستةص ق‬
‫لقال مق خقال‬
‫الك مققإ رورام الم ق اققا ح ق ات ق جققو عملي ق‬
‫لققال لطبيو ق أو ارم الم ق صخصوص ق ارورام ال بقي ق و اققا توغلي ق‬
‫اخإ نسيي الم أو لو و الورم اا من ط قريب مق م اركقا حيويق اقا المق‬
‫اآ ا ستةص‬
‫بوض وظ ة‬
‫ال راحا ن ح مح و وق يقا ي ىلق مضق ع‬
‫الم ‪.‬‬
‫الوقالن ا شققو عا جققو عققالن ب سققتخ ام التطبيقق‬
‫الخالي السرط ني وتقلقي‬
‫لق ا اققنح‬
‫القورم وقق ُلوحظق‬
‫وب لتق لا‬
‫عصقبي أو ع قا اقا‬
‫المختل ق لإلشققو‬
‫المققاي لتق مير‬
‫قق ر الوقالن ا شقو عا علق ىط لق اتقر‬
‫ويسقتخ م الوقالن‬
‫بق جاال المرض عل قي الحي اا خال القثالر عققو الم ضقي‬
‫ُ‬
‫ا شققو عا يوققالن مسق ع بوق الوققالن ال ارحققا وخصوصق اققا ارورام ال بقيق أو يوققالن‬
‫ش ةا اا ح ال أورام ار يم َّ‬
‫الظ ِجر الوصبا وأورام الخاليق التن سقلي أو يوقالن لم قر‬
‫‪-1-‬‬
‫الملخص العربي‬
‫ىيق ف ىا ي ح م الورم والح ج عل ح م الح لا يمق جقو الحق‬
‫وأورام الغ النخ مي ‪.‬‬
‫اقا ارورام السقح ةي‬
‫أمق الوققالن ا شققو عا ال ارحققا ايققو يسققتخ م رعق ع ليق مق ا شققو‬
‫تطلق لمققر‬
‫واح وب ق ع لي عل نسيي الورم اقط وليس عل يإ المق يمق جقو الحق‬
‫اقا الوقالن‬
‫وم أشقير وسق ةإ جق ا الوقالن جقو سقيي‬
‫ا شو عا الو ي بغرض ت مير الورم ني ةي‬
‫م ‪ .‬وق أُستُخ م ج ا الوالن اا ب ي ارمر اا عالن أورام الم الحمي مثإ ارورام‬
‫السققح ةي وي ق لال أورام الغ ق النخ ميق وي ق ب ق يال ي ق اً لل ارحق ‪ .‬أم ق ا ايسققتخ م ج ق ا‬
‫الوققالن ايض ق اققا أورام الم ق الث نوي ق محقق ق ن ق و ي ق اققا ح ق ال‬
‫الوالن م اا ن ح مح و اا م‬
‫مخت ق ر ولك ق جق ق ا‬
‫ارورام ال بقي ‪.‬‬
‫أم الوالن الكيم وي اق لوب ور مس ع من الب اي و لقال لن حق المحق و يوقالن‬
‫وحي ق رورام الم ق لصققووب ى تي ق اه للح ةققإ ال ق موي ال ق م غا وأح ق ر أنواع ق جققو عق ق ر‬
‫التيمواولمي والل ي حق ن ح لحق مق اقا عقالن ارورام ال بقيق وخصوصق عنق ىقت ارنق‬
‫بق ق لوالن ا ش ققو عا حي ققر أ‬
‫ىلق ق ايق ق‬
‫ات ققر بقق ق المرضق ق علق ق قيق ق الحيق ق مق رنق ق‬
‫ب لوالن ا شو عا من ر اً‪.‬‬
‫ل ا يوتبقر الوقالن ا شقو عا والكيمق وي جمق الومقو ال ققري للوال ق‬
‫غيقر ال راحيق‬
‫لموظم أورام الم وخصوص ارورام ال بقي و لال عن ىستخ اميم بشيإ متاام مق ِبق‬
‫الوالن الكيم وي بشيإ مبير واستكم ل بو ا نتي م الوالن ا شو عا‪.‬‬
‫الو ققالن المنق ق عا ج ققو أحق ق وسق ق ةإ الو ققالن الت ققا ظي ققر لمي مق ق أورام المق ق والت ققا‬
‫أوضح‬
‫نت ةي مش و حير يتميا بق رت عل مي م خالي الورم بخصوصي واو لي‬
‫واوق‬
‫ع لي م الح ج اا ن س الوق عل خالي الم ويوتبر الوقالن المنق عا نمق‬
‫َّ‬
‫حسققب ال ارس ق التققا أُ ري ق علي ق ‪ .‬والوققالن المن ق عا ق ق ييققو عققالن من ق عا ِ‬
‫نشققط أو‬
‫عققالن من ق عا سققلبا أو عققالن من ق عا يتبن ق ىسققتخ ام خالي ق من عي ق موين ق والل ق ي ن ق اًر‬
‫م يستخ م ح لي ً‪.‬‬
‫‪-2-‬‬
‫الملخص العربي‬
‫الو ققالن المنق ق عا ِ‬
‫النش ققط يس ققتي ف ىس ققتث ر يق ق ا المن عق ق لق ق ي المق قريض حق ق ار‬
‫ىست ب من عيق مضق‬
‫للقورم و لقال عق طريق لق حق‬
‫التققا أظيققر نت ق ةي واع ق اققا م ق‬
‫أعق ا يبيققر مق المرضق‬
‫موينق‬
‫ويو ق بوقض اللق حق‬
‫عققالن أورام الم ق وتنتظققر الماي ق م ق ال ارس ق عل ق‬
‫أم الوققالن المنق عا السققلبا ايتضققم ىعطق المقريض أ سق م‬
‫موَّ مسبق ً خ رن سم المريض وتسقتي ف جق ه ار سق م المضق‬
‫مض‬
‫خاليق القورم‬
‫وم أشير أنواع عق ر البيڤ سيايوم ب والل ي أظير نت ةي مش و خصوص ً عن ىقتران‬
‫ب لوالن الكيم وي‪ .‬وب لرغم أ الوالن المن عا لم ُييتش ولم ُيستخ م لييو عالن وحيق‬
‫واو ‪.‬‬
‫رورام الم ىال أن سوف ي خ مي ن يوالن مس ع ج م اً َّ‬
‫حير أ أورام الم وخصوص ً ارورام ال بقي تتميا بوع ةي موي ع لي اآ الوالن‬
‫ال َّو ل والي مق واللق ي بق أ ُيسقتخ م‬
‫المض لتكوي اروعي ال موي سييو م الوال‬
‫بش ققيإ يبي ققر لو ققالن أورام المق ق وعقق ق ر البيڤ س ققيايوم ب السقق ل يق قره لق ق تق ق ثير مضق ق‬
‫لتك ققوي اروعيق ق ال مويق ق وأيضق ق يقل ققإ التض ققخم الن ش ققا ح ققو موظ ققم أورام المق ق الت ققا‬
‫أظير ىست ب‬
‫ي لي ا الوق ر ل ا ا لوالن المضق لتكقوي اروعيق ال مويق لق قق ر‬
‫ع لي عل ىيق ف نمو الورم‪.‬‬
‫أم الوالن الچينا ايتم بآستخ ام م‬
‫چينيق مثقإ ‪ RNA‬أو ‪ DNA‬وا خ ليق اخقإ‬
‫چقي‬
‫خالي الورم لتحقي ج ف ُموي وجو ت مير خالي الورم ويتم لال ع طريق ى خق‬
‫ىنتحق ري أو چققي مثققبط للتققورم أو چققي يايق الق ا ع المن عيق لل سققم أو چققي يقلققإ مق‬
‫ق ر الورم عل تكوي أوعي‬
‫موي‬
‫يق‬
‫وحتق ا‬
‫الوقالن الچينقا جقو عقالن تحق‬
‫ال راس ولم يتم تطبيق عل أع ا يبير م المرض ولكن أظير نت ةي مش و اقا جق ه‬
‫ال ارسق ق‬
‫اروليق ق‬
‫ويوتب ققر الو ققالن الچين ققا أحق ق ارس ققلح المت حق ق لمي مق ق أورام المق ق‬
‫او ل وخصوص ً عن ىستخ ام م يإ م الوالن ا شو عا‬
‫وسوف ييو وسيل عالن َّ‬
‫والوالن الكيم وي‪.‬‬
‫‪-3-‬‬
‫الملخص العربي‬
‫أمق ب لنسققب للوققالن اليرمققونا اقق حقق نتق ةي بق جر اققا عققالن أورام الغق النخ ميق‬
‫سوا اا تقليإ ح م الورم أو اقا السقيطر علق ا اقراا اليرمقونا وتوصقيل الق مو التق‬
‫الطبيويق ق ق ب لنس ق ققب ل ق ققلورام الم ق ققرا لليرمونق ق ق‬
‫ومش بي‬
‫السوم توست تي أ‬
‫ال ط ر اا م‬
‫وت ق ققوار ي ق ققإ مق ق ق مح ق ق ق اا الق ق ق وب مي‬
‫عالن ج ه ارورام‪.‬‬
‫ونظ اًر ر أورام الم اةم ً م تكو مصحوب بتورم وتضخم اا نسيي الم المحيط‬
‫بيق ممق يققا ي الق ايق اققا الضققغط اخققإ ال م مق ُمحقِ ث ً الو يق مق ارعقراض لق ا‬
‫اققآ ور ار ويق المثبطق للتققورم جققو ور حيققوي وجق م ق اً حيققر تُسققتومإ تقريبق اققا يققإ‬
‫أورام الم وم أجم ج ه ار وي وأكثرج ىستوم ال جا الكورتييوسقتيروي ا وأجميق عقق ر‬
‫ال ييس ق ميث او وق ق حقق ق‬
‫ج ق ه ار وي ق ن ق و ارة ق اققا تقليققإ التضققخم المحققيط ب ق لورم‬
‫وب لتق لا تقليققإ ارعقراض الن ت ق عنق بشققيإ يق وسقري ولكنيق أيضق مصققحوب بققبوض‬
‫ا ث ر ال نبي مم ىستلام البحر ع ب اةإ لي ه ار وي ييو لي نث ر‬
‫نبي ‪.‬‬
‫بق لرغم مق التقق م الملحقوج اققا ايقم بيولوچيق أورام المق ىال أ التقق م اققا ىط لق اتققر‬
‫بق جاال المرض عل قيق الحيق تقق م بسقيط نوعق ً مق‬
‫والوالن الكيم وي واستخ اميم بشيإ متاام ل أجمي قصقو‬
‫لكق مق اا الوقالن ا شقو عا‬
‫وظيقور بوقض الوال ق‬
‫ال يق التققا أظيققر نتق ةي مشق و يوطققا ارمققإ ليقاال المرض ق وي ولنق نتوقق تق ق م‬
‫وشيال اا م‬
‫عالن أورام الم ‪.‬‬
‫‪-4-‬‬
‫اإلتجاهات الحديثة في العالج غير الجراحي‬
‫ألورام المخ‬
‫رسالة توطئة للحصول على درجة الماﭽيستير في‬
‫األمراض النفسية و العصبية‬
‫مقدمة من‬
‫الطبيب‪ /‬هشام محمد إبراهيم العدروسي‬
‫تحت إشراف‬
‫األستاذ الدكتور‪ /‬محمـد يـاسـر متولـي‬
‫أستاذ األمراض النفسية و العصبية‬
‫كلية الطب – جامعة عني مشس‬
‫الدكتور‪ /‬عمرو عبد المنعم محمد‬
‫مدرس األمراض النفسية و العصبية‬
‫كلية الطب – جامعة عني مشس‬
‫جامعة عين شمس‬
‫كلية الطب‬
‫‪0202‬‬