C H A P T E R
2
Overview of Pathology and Treatment
of Primary Brain Tumors
Herbert B. Newton
Division of Neuro-Oncology, Departments of Neurology and Neurosurgery, Dardinger Neuro-Oncology Center,
Wexner Medical Center at The Ohio State University and James Cancer Hospital and Solove Research Institute,
Columbus, OH, USA
The epidemiology of primary brain tumors (PBTs)
was reviewed in detail in Chapter 1. In this chapter, we
provide an overview of the classification, pathology, and
treatment of the common PBT. PBTs will be diagnosed
in approximately 30,000–35,000 patients in the United
States this year and are associated with significant mor-
bidity and mortality.1–6 Of the estimated 14 patients per
100,000 population that will develop a PBT this year, 6–8
per 100,000 will have a high-grade neoplasm, usually
some form of glioma such as glioblastoma multiforme
(GBM) or anaplastic astrocytoma (AA).
PATHOLOGY OF SELECTED PBTs
The application of appropriate therapeutic strat-
egies is dependent on knowing the type of tumor
affecting a given patient. In addition to assisting with
treatment decisions, the tumor classification and
grade provide important information regarding prog-
nosis. This chapter follows the World Health Orga-
nization (WHO) classification that separates nervous
system tumors into different nosological entities and
assigns a grade of I–IV to each lesion (see Table 1),
with grade I being biologically indolent and grade
IV being biologically most malignant and having
the worst prognosis.7,8 Within the WHO classifica-
tion, tumors of neuroepithelial and meningeal origin
contain the two largest and most clinically relevant
groups of neoplasms.
Tumors of neuroepithelial origin comprise a large and
diverse group of neoplasms, with a mixture of slowly
growing and malignant tumor types (see Table 2).7–9
Handbook of Neuro-Oncology Neuroimaging, Second Edition
http://dx.doi.org/10.1016/B978-0-12-800945-1.00002-1 © 2016 Elsevier Ltd. All rights reserved.
Gliomas (e.g., GBM, AA, oligodendrogliomas, medullo-
blastoma) are the largest subgroup within the neuroepi-
thelial class of neoplasms and are also the most common
type of PBT. Tumors of neuroepithelial origin, and glio-
mas in particular, can grow diffusely within the brain or be
more circumscribed. Diffusely growing tumors are most
common and include the astrocytomas, oligodendroglio-
mas, and mixed oligoastrocytomas. Any of these subtypes
can undergo malignant transformation and degenerate
into the most aggressive form of glioma, the GBM.
Diffuse Astrocytomas. The current WHO classification
divides astrocytomas into diffuse and localized variet-
ies (see Table 3).7–9 The diffuse astrocytomas are intrinsi-
cally invasive and often travel along white matter tracts
deep into normal brain. There are three groups of dif-
fuse astrocytic neoplasms: astrocytoma (WHO grade II;
peak age of 30–39 years), AA (WHO grade III; peak age
of 40–49 years), and GBM (WHO grade IV; peak age of
50–69 years). Diffuse astrocytic tumors can be divided
into fibrillary, protoplasmic, and gemistocytic forms, with
the fibrillary form being most common. The presence of
gemistocytic and protoplasmic cellular variations are
most often seen in WHO grade II tumors. WHO grade II
astrocytomas are considered low-grade tumors and usu-
ally occur in the cerebral white matter. These tumors are
characterized by a relatively uniform population of pro-
liferating neoplastic astrocytes in a fibrillary matrix, with
minimal cellular and nuclear pleomorphism or atypia
(see Figure 1). Tumor margins are poorly delineated and
suggest significant infiltration into surrounding brain.
Mitotic figures are absent and there is no evidence for
vascular hyperplasia. Microcystic change is commonly
noted in all variants of grade II astrocytoma. The Ki-67
9
10 2.  TREATMENT OF PRIMARY BRAIN TUMORS

TABLE 1  WHO Classification: Tumors of the Central Nervous

System
Tumors of neuroepithelial tissue

Tumors of cranial nerves and spinal nerves

Tumors of the meninges

Lymphomas and hemopoietic neoplasms

Germ-cell tumors

Tumors of the sellar region

Cysts and tumor-like lesions

Metastatic tumors

FIGURE 1  WHO grade II fibrillary astrocytoma. Note the neo-

TABLE 2  WHO Classification: Tumors of Neuroepithelial Tissue plastic astrocytes in a fibrillary matrix, with mildly increased cellular-
Astrocytic tumors ity and pleomorphism. No mitoses or hypervascularity are present.
Hematoxylin and eosin staining (H&E); original magnification 200×.
Oligodendroglial tumors

Ependymal tumors

Mixed gliomas

Choroid plexus tumors

Neuronal and mixed neuronal–glial tumors

Pineal parenchymal tumors

Neuroepithelial tumors of uncertain origin

Embryonal tumors

TABLE 3  WHO Classification: Astrocytic Tumors

DIFFUSE ASTROCYTOMAS
FIGURE 2  WHO grade III fibrillary astrocytoma (AA). The tumor
Astrocytoma (WHO grade II)
is more densely cellular than grade II, with significant cellular and
Fibrillary nuclear pleomorphism and atypia. Mitotic figures are evident. H origi-
nal magnification 200×.
Protoplasmic

Gemistocytic
Anaplastic astrocytoma (WHO grade III)
Glioblastoma multiforme (WHO grade IV)
Giant cell glioblastoma
Gliosarcoma
LOCALIZED ASTROCYTOMAS (WHO GRADE I)
Pilocytic astrocytoma
Pleomorphic xanthoastrocytoma
Subependymal giant cell astrocytoma
labeling index of WHO grade II astrocytomas is typically
less than 4%, with a mean of approximately 2.0–2.5%.
Higher-grade diffuse astrocytomas include AA (WHO
grade III) and GBM (WHO grade IV), as well as the GBM
variants giant cell glioblastoma and gliosarcoma (WHO
grade IV) (see Table 3).7–10 Anaplastic astrocytomas are
similar to grade II tumors, except for the presence of
more prominent cellular and nuclear pleomorphism and
atypia and mitotic activity (see Figure 2). In addition,
grade III and IV tumors usually do not stain as intensely
or as homogeneously with glial fibrillary acidic protein
(GFAP). According to WHO criteria, the critical feature
that upgrades a grade II tumor to an AA is the presence of
mitotic activity, with anaplastic tumors having Ki-67 indi-
ces in the range of 5–10% in most cases. Other features of
anaplasia can be present, such as multinucleated tumor
cells, abnormal mitotic figures, and regions of vascular
proliferation. Necrosis is absent in grade III astrocytomas.
Glioblastoma multiforme is classified as a WHO grade
IV tumor and has histological features similar to those
of AA, but with more pronounced anaplasia (see Figure
3(A)).7–10 The presence of microvascular proliferation
and/or necrosis in an otherwise malignant astrocytoma

I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS

 PATHOLOGY OF SELECTED PBTs 11

(A) (B)

(C)

FIGURE 3  WHO grade IV fibrillary astrocytoma (GBM). (A) A highly cellular tumor with marked cellular and nuclear pleomorphism, numer-
ous mitoses, giant cells (H original magnification 400×); (B) dense vascular proliferation (H original magnification 200×); and (C) regions of necro-
sis with pseudopalisading tumor nuclei (H original magnification 100×).

upgrades the tumor to a GBM. Vascular proliferation is
defined as blood vessels with “piling up” of endothelial
cells, including the formation of glomeruloid vessels (see
Figure 3(B)). The glomeruloid vessels can form undulat-
ing garlands that surround necrotic zones in some cases.
Necrosis can be noted in large amorphous areas, which
appear ischemic in nature, or can appear as more ser-
piginous regions with surrounding palisading tumor
cells (i.e., perinecrotic pseudopalisading; see Figure
3(C)). Necrosis with nuclear pseudopalisading is essen-
tially pathognomonic for GBM. Other features of GBM
that are typically prominent include marked cellular and
nuclear pleomorphism and atypia, mitotic figures and
multinucleated giant cells, and pronounced infiltrative
capacity into the surrounding brain. Labeling indices
with Ki-67 are usually in the range of 15–20%, but can be
much higher in some tumors.
Localized Astrocytomas. In the WHO classification, the
localized astrocytomas include the pilocytic astrocytoma
(WHO grade I), pleomorphic xanthoastrocytoma (PXA;
WHO grade II), and the subependymal giant cell astro-
cytoma (WHO grade I).7–10 Pilocytic astrocytomas are
slow-growing, relatively circumscribed tumors that usu-
ally occur in children (peak age 10–12 years) and young
adults. These tumors have a predilection for the cerebel-
lum, optic nerves and optic pathways, and hypothala-
mus. The distinctive histological feature is the presence
of cells with slender, elongated nuclei and thin, hair-like
(i.e., piloid), GFAP-positive, bipolar processes. These cells
are found in a biphasic background, which consists of
dense fibrillary regions alternating with loose, microcys-
tic areas. Labeling index studies with Ki-67 report values
of 0.5–1.5% in most tumors. The PXA is a supratentorial
tumor with a predilection for the superficial temporal
lobes that usually occurs in younger patients (mean age
15–18 years) with a long-standing history of seizure activ-
ity.7–10 On histological examination, PXA demonstrates
significant pleomorphism, with numerous atypical giant
cells and astrocytes with prominent nucleoli.11 Also pres-
ent are large foamy (xanthomatous) cells with lipidized
cytoplasm that express GFAP. Subependymal giant cell
astrocytoma is an indolent, slowly growing tumor that
typically arises in the walls of the lateral ventricles and is
almost invariably associated with tuberous sclerosis.7–10
Oligodendrogliomas and Oligoastrocytomas. Oligoden-
drogliomas are a form of diffuse glioma that can be of
pure or mixed histology and are classified as WHO grade
II or III.7–10 They typically occur in young to middle-aged
adults (peak age 35–45 years) with a history of seizures,
within the white matter of the frontal and temporal lobes.
Pure low-grade oligodendroglial tumors (WHO grade II)
are characterized histologically by a moderately cellu-
lar, monotonous pattern of cells with round nuclei and
perinuclear halos (the classic “fried-egg” appearance;
see Figure 4).12 The perinuclear halos are an artifact of
the formalin fixation process of the tumor tissue. Foci of

I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS

12 2.  TREATMENT OF PRIMARY BRAIN TUMORS
calcification are frequent and can be quite dense in some
cases. Delicately branching blood vessels are prominent
(i.e., “chicken-wire” vasculature), but do not display
endothelial proliferation. Oligodendrogliomas have a
pronounced invasive capacity and are known to invade
the gray and white matter diffusely, with a strong ten-
dency to form secondary structures of Scherer, in partic-
ular perineuronal satellitosis. Mitoses are absent or rare
and necrosis is not present. Labeling studies with Ki-67
usually demonstrate indices less than 5%, with a mean of
approximately 2%. The diagnosis of an anaplastic oligo-
dendroglioma (WHO grade III) requires the presence of
additional histologic features, including a higher degree
of cellularity and mitotic activity, vascular endothe-
lial hyperplasia, nuclear pleomorphism, and regions of
necrosis (see Figure 5(A) and (B)). These tumors behave
FIGURE 4  WHO grade II oligodendroglioma. This image demon-
strates the classic features of typical oligodendroglioma, with moder-
ate cellularity and numerous round cells with the “fried-egg” pattern
of perinuclear halos and delicate “chicken-wire” vasculature. H origi-
nal magnification 400×.
(A)
FIGURE 5  WHO grade III oligodendroglioma. A more densely cellular tumor with prominent cellular and nuclear pleomorphism, mitotic
activity (A), and increased vascularity (B). H original magnification 400×.
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
in a more aggressive fashion, with a higher proliferative
rate (Ki-67 labeling index >5%) and capacity for invasion
of surrounding brain. Mixed oligoastrocytomas can be
classified as WHO grade II or III tumors.7–10 Distinct pop-
ulations of neoplastic oligodendroglial cells and astro-
cytes can be identified within the mass that have features
similar to pure versions of the tumor. The percentage of
each cell population can be quite variable, with an even
mixture of cell types or with one cell type predominating.
Advances in molecular neuropathology have begun
to clarify the biological underpinnings of variability in
response to treatment of oligodendrogliomas.12–14 The
majority of tumors demonstrate genetic losses on chro-
mosome 1p (40–92%) and/or 19q (50–80%). There is a
strong predilection for deletions of 1p and 19q to occur
together, but in some tumors they can be singular events.
Patients with oligodendrogliomas that contain deletions
of 1p and 19q are consistently more responsive to irra-
diation and chemotherapy and have an overall median
survival of 8–10 years. In contrast, patients with tumors
that do not have deletion of 1p and 19q are more resis-
tant to all forms of therapy and have an overall median
survival of only 3–4 years.
Medulloblastoma and Other Embryonal Tumors. Embry-
onal tumors are a group of aggressive, malignant neo-
plasms that usually affect children. They are classified
by the WHO as grade IV in all cases (see Table 4).7–10
All embryonal tumors share the common features of
high cellularity, frequent mitoses, regions of necrosis,
and a propensity for metastases along cerebrospinal
fluid (CSF) pathways. Medulloblastoma is the most
common of the embryonal tumors and is considered a
primitive neuroectodermal tumor (PNET) of the cerebel-
lum. It usually arises in the midline in children, within
the cerebellar vermis, whereas in adults it is more likely
to have an off-center location within the cerebellar
(B)
 PATHOLOGY OF SELECTED PBTs 13
hemispheres. The typical medulloblastoma is densely TABLE 5  WHO Classification: Tumors of the Meninges
cellular and composed of undifferentiated cells with
TUMORS OF MENINGOTHELIAL CELLS (MENINGIOMAS)
hyperchromatic, oval to carrot-shaped nuclei with scant
cytoplasm (see Figure 6).9,15 The nuclei have a tendency Meningothelial
to mold against one another. Mitoses and single cell Fibrous (fibroblastic)
necrosis are frequently present. Evidence of anaplasia is
Transitional (mixed)
variable and may include increased nuclear size, abun-
dant mitoses, and the presence of large cells or similar Psammomatous
aggressive cellular morphology. Some tumors may dis- Angiomatous
play immunohistochemical and morphological evidence
Microcystic
for differentiation along neuronal, glial, or mesenchymal
lines. Medulloblastomas are highly proliferative tumors, Secretory
with Ki-67 labeling indices ranging from 15% to 50%. Lymphoplasmacyte rich
Meningioma and Other Tumors of the Meninges. Tumors
Metaplastic
of the meninges comprise a large and diverse group of
neoplasms that mostly have meningothelial or mesenchy- Clear cell
mal, nonmeningothelial origins (see Table 5).8,9 The most Chordoid
common primary tumor of this group is the meningioma
Atypical

TABLE 4  WHO Classification: Embryonal Tumors Papillary

Rhabdoid
Medulloepithelioma
Anaplastic
Ependymoblastoma
MESENCHYMAL, NONMENINGOTHELIAL TUMORS
Medulloblastoma
Lipoma
  Desmoplastic medulloblastoma
Angiolipoma
  Large-cell medulloblastoma
Hibernoma
 Medullomyoblastoma
Liposarcoma (intracranial)
  Melanotic medulloblastoma
Solitary fibrous tumor
Supratentorial PNET
Fibrosarcoma
 Neuroblastoma
Malignant fibrous histiocytoma
 Ganglioneuroblastoma
Leiomyoma
Atypical teratoid/rhabdoid tumor
Leiomyosarcoma

Rhabdomyoma

Rhabdomyosarcoma

Chondroma

Chondrosarcoma

Osteoma

Osteosarcoma

Osteochondroma

Hemangioma

Epithelioid hemangioendothelioma

Hemangiopericytoma

Angiosarcoma
FIGURE 6  WHO grade IV medulloblastoma. Note the dense cel-
lularity and presence of undifferentiated cells with hyperchromatic, Kaposi sarcoma
oval to carrot-shaped nuclei with scant cytoplasm. The nuclei have a
tendency to mold against one another. H original magnification 200×. Continued

I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS

14 2.  TREATMENT OF PRIMARY BRAIN TUMORS
TABLE 5  WHO Classification: Tumors of the Meninges—cont’d
PRIMARY MELANOCYTIC LESIONS
Diffuse melanocytosis
Melanocytoma
Malignant melanoma
Meningeal melanomatosis
FIGURE 7  WHO grade II meningioma. The tumor demonstrates
a moderately dense, uniform pattern of cells with oval-shaped nuclei
and the presence of many cellular whorl patterns. H original magnifi-
cation 200×.
(18–20% of intracranial tumors), which has meningothe-
lial cell origins and is composed of neoplastic arachnoi-
dal cap cells of the arachnoidal villi and granulations.
Meningiomas can occur anywhere within the intracra-
nial cavity, but favor the sagittal area along the superior
longitudinal sinus, over the lateral cerebral convexities,
at the tuberculum sellae and parasellar region, the sphe-
noidal ridge, and along the olfactory grooves. Numerous
histologic variants of meningioma are described and
recognized by the WHO (see Table 5). However, the his-
topathological description of most of these variants has
no bearing on the clinical behavior of the tumor. Menin-
gioma subtypes that have a more indolent nature and low
risk for aggressive growth or recurrence are classified as
WHO grade I and include the meningothelial, fibrous/
fibroblastic, transitional (mixed), secretory, psammoma-
tous, angiomatous, microcystic, lymphoplasmocyte-rich,
and metaplastic variants.16,17 Of this group, the menin-
gothelial, fibrous, and transitional variants are most fre-
quently diagnosed. The histological features common to
most low-grade meningiomas are the presence of whorls
(tightly wound, rounded collections of cells), psammoma
bodies (concentrically laminated mineral deposits that
often begin in the center of whorls), intranuclear pseudoin-
clusions (areas in which pink cytoplasm protrudes into a
nucleus to produce a hollowed-out appearance), and occa-
sional pleomorphic nuclei and mitoses (see Figure 7).16,17
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
FIGURE 8  WHO grade III anaplastic meningioma. This higher
power view demonstrates increased nuclear pleomorphism and fre-
quent mitoses. H original magnification 400×.
Meningothelial meningiomas are composed of lobules of
typical meningioma cells, with minimal whorl formation.
The tumor cells are uniform in shape, with oval nuclei
that may show central clearing. Fibrous variants have
spindle-shaped cells resembling fibroblasts that form
parallel and interlacing bundles within a matrix of col-
lagen and reticulin.
Meningioma subtypes that are more likely to display
aggressive clinical behavior and to recur are classified
by the WHO as grade II (atypical, clear cell, chordoid)
and grade III (rhabdoid, papillary, anaplastic).8,9,16,17 On
histological examination, all of the grade II tumors are
likely to demonstrate increased cellularity, more fre-
quent mitoses, diffuse or sheetlike growth, nuclear pleo-
morphism and atypia, and evidence for micronecrosis.
Grade III tumors such as anaplastic meningioma show
features consistent with frank malignancy, including a
high mitotic rate, advanced cytological atypia, nuclear
pleomorphism, and necrosis (see Figure 8). Invasion of
underlying brain is frequently noted in grade III menin-
giomas, but can also occur in lower grade variants.
Proliferation studies using Ki-67 demonstrate labeling
indices ranging from 8% to 15%.
Primary Central Nervous System Lymphoma. Primary
central nervous system lymphomas (PCNSLs) are
malignant tumors classified as WHO grade IV that
affect adults in the sixth or seventh decade of life.8,9
They are often multifocal and usually arise in the deep
supratentorial white matter, with a predilection for the
periventricular region and basal ganglia. PCNSLs are
composed of a clonal expansion of neoplastic lympho-
cytes, typically of the diffuse, large-cell, or immuno-
blastic variety. In 95% of the tumors, the cells have a B
cell lineage, often with monoclonal IgMκ production.
On histological examination, PCNSLs display a peri-
vascular cellular orientation, with expansion of vessel
walls and reticulin deposition (see Figure 9).18 Regions
 RADIATION THERAPY OF PBTs
FIGURE 9  WHO grade IV primary CNS lymphoma. Note the pres-
ence of neoplastic lymphocytes in an angiocentric growth pattern, with
nuclear pleomorphism and mitoses. H original magnification 100×.
of necrosis are common, especially if steroids have
been administered prior to the biopsy. The lympho-
matous cells are noncohesive and usually have large,
irregular nuclei, prominent nucleoli, and scant cyto-
plasm. From the perivascular region, tumor cells are
noted to invade the surrounding brain parenchyma,
either in compact cellular aggregates or as singly infil-
trating tumor cells. PCNSLs are highly proliferative
tumors, with Ki-67 labeling indices ranging from 20%
to 50% in most studies. The diagnosis can be confirmed
by immunohistochemical positivity for leukocyte com-
mon antigen (CD45) and specific B cell markers (CD19,
CD20, and CD79a).
SURGICAL THERAPY OF PBTs
Surgical intervention is the most common form of
treatment for PBTs and is an important aspect of ini-
tial therapy in most patients. Indications for surgery
include reduction of tumor burden, alleviation of mass
effect, control of seizures and reversal of neurologi-
cal deficit, confirmation of the histological diagnosis,
diversion of CSF by shunting procedures in selected
cases, and the introduction of local antineoplastic
agents.1,19,20 Advances in neurosurgical technology
offer new approaches to tumor removal, such as frame-
based and frameless stereotactic biopsy, preoperative
functional magnetic resonance imaging (MRI) and
intraoperative cortical mapping, neuronavigation and
tumor resection in the awake patient, and the use of
intraoperative MRI.21–23 These techniques allow the
surgeon to more carefully delineate tumor margins
and to preserve surrounding regions of eloquent brain
(e.g., Broca’s area, primary motor cortex) and delicate
vascular structures, while performing a more aggres-
sive and thorough tumor resection. Complete removal
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
15
of benign tumors such as meningioma, pilocytic astro-
cytoma, and schwannomas can be curative. For malig-
nant tumors (i.e., GBM, AA), although the lack of a
prospective, controlled randomized clinical trial still
fosters debate in the literature, most neurosurgeons rec-
ommend a near-total or gross-total resection, whenever
possible, of all enhancing tumor volume and regionally
infiltrated brain as defined on T2-weighted or FLAIR
MRI sequences. Gross-total tumor resection is not cura-
tive for these tumor types, but has been associated with
longer overall and progression-free survival (PFS) in
several studies, as well as improved neurological qual-
ity of life.24,25 For tumors that are diffusely infiltrative
or multifocal, a stereotactic biopsy is more likely to pre-
serve neurological function than an attempt at resection
and, in most cases, will be able to provide a histological
diagnosis to guide further treatment. The accuracy of
stereotactic biopsy is further improved when the region
of interest is defined by contrast enhancement on MRI
or abnormal signal on MRI spectroscopy or positron
emission tomography.
RADIATION THERAPY OF PBTs
External beam fractionated radiation therapy is an
appropriate form of treatment for virtually all patients
with high-grade gliomas (i.e., GBM, AA, anaplastic oli-
godendroglioma (AO), medulloblastoma), as well as for
selected low-grade PBTs that are surgically inaccessible
or have progressed after initial resection.1,26–29 Numer-
ous randomized controlled trials have demonstrated a
survival benefit for high-grade glioma patients receiving
surgical resection and irradiation in comparison to resec-
tion alone (approximately 34–38 weeks vs 14–18 weeks,
respectively). The mechanism of cell death appears to
be the production of DNA strand damage by ionizing
radiation and the generation of highly reactive oxy-
gen radicals that induce further DNA damage and dis-
rupt cellular processes. Sublethal or mortal damage to
endothelial cells in tumor vessels may also be of impor-
tance. The standard approach is administered in the
early postoperative phase and initially uses conformal
radiation ports that encompass the T2-weighted target
with a margin of 1–3 cm, using a dose of approximately
4500–4700 cGy in 180- to 200-cGy daily fractions. After
this portion has been completed, a “cone down” is per-
formed, targeting the T1-weighted contrast-enhancing
volume of the tumor with a 1- to 3-cm margin, bringing
the total dose to approximately 6000 cGy. Irradiation is
performed over the course of 6–7 weeks, with the patient
receiving treatment 5 days per week. Radiation therapy
schedules can sometimes be modified with hypofrac-
tionation and/or an abbreviated treatment course for
elderly patients or for those with a low performance
16 2.  TREATMENT OF PRIMARY BRAIN TUMORS
status, while maintaining a similar level of toxicity and
overall survival.30,31 More aggressive approaches to irra-
diation using hyperfractionation schemes have not been
shown to improve tumor control and, in some reports,
have been associated with worse outcomes.28 Other
techniques to increase localized radiation doses to the
tumor resection cavity, such as brachytherapy with per-
manent or temporary radioactive seeds, have also had
disappointing results in controlled trials.32 In addition
to the cranial dosage, spinal-axis radiation therapy is
necessary for tumors that often seed the meninges, such
as medulloblastoma, pineoblastoma, and anaplastic
ependymoma.
Stereotactic radiosurgery, using a linear accelerator-
based system (e.g., Cyberknife®) or a Co60-based system
(e.g., Gamma Knife®) to deliver a single (or a few) high-
dose radiation fraction(s) to a defined volume using
stereotactic localization, is another method to boost
radiation doses in the tumor bed of a newly diagnosed
or recurrent glioma, while sparing normal surrounding
tissues.33–35 Because of the diffuse, infiltrative nature of
the growth pattern of these tumors, the application of
focal treatment modalities such as radiosurgery remains
controversial. Retrospective and single-armed, uncon-
trolled prospective trials suggest an improvement in
local tumor control rates and survival when using either
radiosurgical system. However, these results were not
been confirmed in the randomized, controlled trial of
radiosurgery for GBM reported by the Radiation Ther-
apy Oncology Group (RTOG 93-05).35,36 In this study,
203 GBM patients were randomized to receive radio-
surgery followed by conventional irradiation (60 Gy)
and intravenous carmustine chemotherapy (80 mg/m2/
day × 3 days every 8 weeks) or irradiation plus chemo-
therapy alone. The median survival for the radiosurgi-
cal and conventional treatment groups were 13.5 and
13.6 months, respectively (p = 0.5711). In addition, the
2- and 3-year survival rates and patterns of failure were
similar between groups. There was no difference in
general quality of life or retention of cognitive function
between groups.
CHEMOTHERAPY OF PBTs
Chemotherapy is used as an adjunctive treatment
for malignant PBTs (i.e., mostly high-grade gliomas—
GBM, AA) and for selected low-grade gliomas that
progress through initial surgical resection and irradia-
tion.1,37–40 The addition of chemotherapy has resulted in
modest improvements in the survival of patients with
malignant glioma, as demonstrated by two detailed
meta-analyses.41,42 Over the past two decades and until
recently, nitrosourea alkylating drugs such as carmus-
tine and lomustine (CCNU) were considered the most
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
effective chemotherapeutic agents for these tumors.37,38
Other agents with mild activity included procarbazine
(administered alone or in combination with CCNU and
vincristine), cisplatin, etoposide, carboplatin, and cyclo-
phosphamide. For the treatment of PCNSL, methotrex-
ate has been shown to be the most active agent, either
alone or in combination with other drugs (e.g., cytara-
bine, rituximab).43
Since 2005, the focus has been on the second-genera-
tion alkylating agent temozolomide (TZM), which has
an activity profile superior to those of the nitrosoureas
and other agents. Temozolomide is an imidazotetrazine
derivative of the alkylating agent dacarbazine, with activ-
ity against systemic and CNS malignancies.37,38,44–47 The
drug undergoes chemical conversion at physiological
pH to the active species 5-(3-methyl-1-triazeno)imidaz-
ole-4-carboxamide. Temozolomide exhibits schedule-
dependent antineoplastic activity by interfering with
DNA replication through the process of methylation.
The methylation of DNA is dependent on the forma-
tion of a reactive methyldiazonium cation, which inter-
acts with DNA at the following sites: N7-guanine (70%),
N3-adenine (9.2%), and O6-guanine (5%). Because TZM
is stable at acid pH, it can be taken orally in capsules.
Oral bioavailability is approximately 100%, with rapid
absorption of the drug. In addition, TZM has excellent
penetration of the blood–brain barrier and brain tumor
tissue.
Initial studies of TZM were in patients with recurrent
AA and GBM and suggested significant activity.37,38,44–47
Subsequent larger studies demonstrated unequivocal
efficacy in the recurrent setting. The first study evalu-
ated the use of TZM (150–200 mg/m2/day × 5 days every
28 days) in a series of 162 patients with recurrent malig-
nant gliomas, including 97 patients with AA.48 In the AA
cohort, there were 6 patients with complete response
(CR), 27 with partial response (PR), and another 31 with
stable disease (SD) (CR + PR + SD = 66%). The response
rate was similar in patients that had failed prior chemo-
therapy or were chemotherapy-naïve. Median overall
PFS was 5.4 months, with 6- and 12-months PFS rates of
46% and 24%, respectively. The median overall survival
was 13.6 months, with 6- and 12-months survival rates of
75% and 56%, respectively. A similar comparative phase
II trial evaluated the activity of TZM versus procarba-
zine (125–150 mg/m2/day × 28 days every 8 weeks) in a
cohort of 225 patients with GBM at first relapse.49 Over-
all response rates (PR + SD) were significantly higher for
patients in the TZM cohort (45.6% vs 32.7%; p = 0.049).
Treatment with TZM resulted in a significant improve-
ment in median PFS (12.4 weeks vs 8.32 weeks; p = 0.0063)
and 6-month PFS (21% vs 8%; p = 0.008) in comparison to
procarbazine. In addition, the 6-month overall survival
rate was significantly higher for patients in the TZM arm
of the study (60% vs 44%; p = 0.019).
 CHEMOTHERAPY OF PBTs
Temozolomide has also been applied to GBM patients
in the “up-front” setting by Stupp and colleagues in a
set of phase II and III studies, in combination with stan-
dard external beam irradiation and monthly adjuvant
chemotherapy.37,38,50,51 For the phase III study, a total of
573 patients were randomly assigned to receive radia-
tion alone (6000 cGy; 200 cGy/day × 5 days/week for
6 weeks) or radiotherapy in combination with daily TZM
(75 mg/m2/day × 7 days/week for 6 weeks).51 After the
completion of irradiation, each patient in the chemo-
therapy arm went on to receive six cycles of adjuvant
single-agent TZM (150–200 mg/m2/day × 5 days, every
28 days). The overall median survival was 14.6 months
for the radiotherapy plus TZM cohort and 12.1 months
for the cohort that received irradiation alone, for an
overall median survival benefit of 2.5 months. The
unadjusted hazard ratio (HR) for death due to the
GBM for the radiotherapy plus TZM cohort was 0.63
(p < 0.001, log-rank test). The 2-year survival rate was
26.5% for the chemoradiation cohort and 10.4% for the
cohort receiving radiotherapy alone. Responsiveness to
chemoradiation and overall survival were found to cor-
relate strongly with the presence of promoter methyla-
tion of the methylguanine-methyltransferase (MGMT)
gene, which is important for tumor cell resistance to
radiotherapy and chemotherapy. Since the publication
of this report, chemoradiation using low-dose TZM,
followed by adjuvant monthly TZM, has become FDA
approved and is now the “standard of care” for newly
diagnosed GBM patients in the United States and
around the world. In a 5-year follow-up of this cohort of
patients, Stupp and colleagues report a persistent and
significant difference in survival between the group of
patients that received radiotherapy and TZM versus
the group that received radiotherapy alone.52 For the
chemoradiation group, overall survival at 4 and 5 years
was 12.1% and 9.8%, respectively. In contrast, the radio-
therapy-alone group had 4- and 5-year overall surviv-
als of 3.0% and 1.9%, respectively. The differences in
overall survival were highly significant, with a HR of
0.60 (p < 0.0001). Methylation of the MGMT promoter
region was still a very strong predictor of response to
TZM chemotherapy.
Dose-intensive or dose-dense schedules of TZM
(e.g., 7  days on/7  days off, 3  weeks on/1  week off)
have also been under investigation, because labora-
tory studies suggest that the higher cumulative dose
may result in improved efficacy through augmented
depletion of MGMT in tumor cells.53 This premise
was tested by the RTOG, in the RTOG-0525 phase III
trial, in a cohort of 833 patients with newly diagnosed
GBM.54 Patients were treated with standard surgical
resection and chemoradiation, and then randomized
to receive either conventional TZM (5 days per month;
150–200 mg/m2/day) or dose-dense TZM (21  days
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
17
on/7 days off; 75–100 mg/m2/day), for a total of 6–12
cycles. The two treatment groups were not statistically
different at final analysis in terms of median overall
survival (16.6 vs 14.9 months; HR = 1.03) or median PFS
(5.5 vs 6.7 months; HR = 0.87). MGMT promoter meth-
ylation was associated with improved overall survival
(21.2 vs 14 months; HR = 1.74), PFS (8.7 vs 5.7 months;
HR = 1.63), and response rate.
Angiogenesis is a tightly controlled process that
involves growth and maintenance of blood vessels
within tissues and organs.55–58 A delicate equilibrium
exists between positive angiogenic factors (e.g., vas-
cular endothelial growth factor (VEGF), transform-
ing growth factor-β (TGF-β)) and inhibitory factors
(e.g., thrombospondin-1, angiostatin, endostatin).55–58
These factors interact with specific receptors on endo-
thelial cells and the extracellular matrix, such as VEGF
receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, TIE1, and
TIE2.57 There are several important stimuli for conver-
sion to the angiogenic phenotype in GBM. The pres-
ence of hypoxia induces upregulation of secretion of
VEGF and expression of VEGFRs in tumor endothelial
cells and surrounding regional vasculature.57 Another
critical element for the switch to the angiogenic phe-
notype is overactivity of the major growth factor sig-
naling pathways and loss of certain tumor suppressor
genes.59 Overexpression and excessive activity of
platelet-derived growth factor (PDGF), epidermal
growth factor (EGF), fibroblast growth factor, Ras,
TGF-α, and TGF-β are critical to the development of
the angiogenic phenotype.60–62 In addition to growth
factor activity, internal signal transduction mediators
also appear to play a role in the angiogenic phenotype.
The PI3K/Akt/PTEN signaling pathway is involved
in the regulation of angiogenesis through the control
of expression of VEGF, hypoxia-inducible factor-1,
and thrombospondin-1.63–65
Numerous investigators have begun to focus on treat-
ment approaches that capitalize on the prominence
of VEGF signaling in solid tumor angiogenesis.95 The
most promising approaches include monoclonal anti-
bodies against VEGF (e.g., bevacizumab) and VEGFR
(e.g., IMC-1C11, DC101).59,66–68 Bevacizumab (Avastin™)
has advanced the farthest in terms of preclinical evalu-
ation and clinical trials.69,70 Bevacizumab is a human-
ized IgG1 monoclonal antibody that is specific for all
isoforms of VEGF, preventing their binding to VEGFR.
It has demonstrated significant activity in preclinical
studies against a wide variety of solid tumors, includ-
ing gliomas, as a single agent and in combination with
conventional chemotherapy.71–73
The first report of the use of bevacizumab for brain
tumor patients was by Stark-Vance in 2005, who treated
21 patients with malignant gliomas with bevacizumab
in combination with irinotecan.74 The response rate was
18 2.  TREATMENT OF PRIMARY BRAIN TUMORS
an impressive 43%, although there were two treatment-
related deaths (intracranial hemorrhage, intestinal per-
foration). Based on this promising preliminary work,
Vredenburgh and colleagues organized a prospec-
tive phase II trial of bevacizumab and irinotecan for
patients with recurrent malignant gliomas.75 Thirty-two
patients were enrolled (GBM 23; anaplastic tumors 9)
and received intravenous bevacizumab (10 mg/kg) and
irinotecan (340 mg/m2 on enzyme-inducing antiepilep-
tic drugs (EIAED), 125 mg/m2 not on EIAED) every 2
weeks. Radiographic responses were noted in 20 of 32
patients (63%; CR 1, PR 19), including 14 of 23 in the
GBM cohort and 6 of 9 in the anaplastic glioma sub-
group. The median overall PFS was 23 weeks: 20 weeks
in GBM patients and 30 weeks in patients with anaplas-
tic tumors. The 6-month PFS and overall survival rates
were 38% and 72%, respectively. In updated reports
from 68 patients (GBM 35; anaplastic tumors 33) the
MRI response rate was similar (59%).76,77 For the GBM
cohort the 6-month PFS was 46%, with a 6-month over-
all survival of 77%. For the anaplastic glioma subgroup,
the 6-month PFS rate was 61%, with a median PFS of
42 weeks. Eight patients were taken off the study for
thrombotic complications, including pulmonary emboli
(4), deep venous thrombosis (2), thrombotic throm-
bocytopenic purpura (1), and thrombotic stroke (1).
The preliminary use of bevacizumab and irinotecan at
other institutions resulted in similar results, in terms
of MRI response rates, time to progression, and overall
survival.73,78–82 The Duke group has also performed a
phase II study of bevacizumab and irinotecan that was
restricted to only patients with recurrent grade III glio-
mas (25 AA, 8 AO).83 There were two cohorts of patients:
the first group of 9 patients received the standard com-
bination regimen every 2 weeks, whereas the second
group received bevacizumab (15 mg/kg every 3 weeks)
and irinotecan (days 1, 8, 22, 29 of each cycle; 340 mg/m2
on EIAED, 125 mg/m2 on NEIAED) on a 6-week cycle.
Objective responses were noted in 29 patients (61%
with at least a PR). The 6-month PFS and overall sur-
vival rates were 55% and 79%, respectively. There was
no difference in PFS or survival rates between the two
treatment cohorts. Although bevacizumab has been well
tolerated by the majority of patients, severe toxicity can
occur, including hypertension, proteinuria, arterial and
venous thromboembolic events, hemorrhage, gastroin-
testinal perforation, and impaired wound healing.84
The results of the BRAIN trial were reported by Fried-
man and colleagues in 2009.73,85 This study was a phase
II, multicenter, open-label, noncomparative trial evaluat-
ing the efficacy of bevacizumab, alone or in combination
with irinotecan, in a group of 167 patients with GBM in
first or second relapse. Patients were randomly assigned
to receive bevacizumab (10 mg/kg) as a single agent
or in combination with irinotecan (340 or 125 mg/m2,
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
depending on EIAED or NEIAED), on an every 2-weeks
schedule. The primary endpoints for the study were
6-month PFS and objective response rate on follow-up
MRI, with secondary endpoints of safety and overall
survival. The 6-month PFS rates in the bevacizumab
alone and bevacizumab plus irinotecan groups were
42.6% and 50.3%, respectively. Objective response rates
on follow-up MRI were 28.2% for the bevacizumab alone
cohort and 37.8% for the bevacizumab plus irinotecan
group. Median PFS times for the bevacizumab alone
and bevacizumab plus irinotecan cohorts were 4.2 and
5.6 months, respectively. The overall survival times were
also similar between the single-agent bevacizumab and
the bevacizumab plus irinotecan groups (9.2 months vs
8.7 months). There was a trend for patients on cortico-
steroids at the beginning of the trial to remain on stable
or decreasing doses over time.86 Grade 3 or 4 toxicity
was more frequent in the bevacizumab plus irinotecan
group (65.8%) in comparison to those receiving bevaci-
zumab alone (46.4%). The most common adverse events
were hypertension, fatigue, neutropenia, and seizures.
Intracranial hemorrhage was uncommon in both groups
(2.4% bevacizumab alone, 3.8% bevacizumab plus irino-
tecan; 5 total patients, only 1 was grade 4). The authors
concluded that bevacizumab, alone or in combination
with irinotecan, was active against recurrent GBM, with
6-month PFS rates that were far superior to the expected
15% rate for salvage chemotherapy and irinotecan alone.
Clinicians have begun to evaluate the safety and
feasibility of using bevacizumab in combination with
temozolomide during chemoradiation in newly diag-
nosed patients with high-grade gliomas.73,87,88 An early
pilot study of bevacizumab (10 mg/kg every 2 weeks)
in combination with temozolomide (75 mg/m2 dur-
ing irradiation, followed by 150–200 mg/m2 × 5 days
every 4 weeks) was performed by Lai and colleagues
in 10 patients with newly diagnosed GBM.87 The tox-
icity was considered to be acceptable and consisted of
fatigue, myelotoxicity, wound breakdown, DVT/PE,
and one case of radiation-induced optic neuropathy.
Preliminary efficacy analysis suggested an encourag-
ing mean PFS (range 15–45 weeks). A similar feasibil-
ity study from Narayana et al. evaluated 15 patients
with high-grade glioma, with the adjuvant therapy
phase planned over 1 year (temozolomide 150 mg/m2/
day).88 Thirteen patients (86.6%) completed the entire
year of adjuvant treatment; radiographic responses
were noted in 13 of 14 assessable patients (92.8%).
The 1-year PFS and overall survival rates were 59.3%
and 86.7%, respectively. Using a more aggressive
approach, Vredenburgh et al. treated 75 patients with
newly diagnosed GBM with standard chemoradia-
tion plus bevacizumab (10 mg/kg every 2 weeks), fol-
lowed by adjuvant temozolomide (200 mg/m2 × 5 days
every month) in combination with bevacizumab
 Molecular or “Targeted” Treatment
and irinotecan (340  mg/m2 on EIAED, 125  mg/m2
on NEIAED) every 2 weeks.89 The median PFS for the
entire cohort was 14.2 months, with a median overall
survival of 21.2 months. At 16-month follow-up, the
overall survival rate was 65%. Another update by the
Duke group reports the results from 125 newly diag-
nosed GBM patients who were treated with standard
chemoradiation and temozolomide, in addition to bev-
acizumab (10 mg/kg intravenously every 2 weeks).90
Overall, the combination of temozolomide and bevaci-
zumab was tolerated well in the majority of patients,
with 96% completing the full course of chemoradiation
and 90% able to continue on with treatment into the
adjuvant chemotherapy phase. Toxicities associated
with treatment discontinuation included pulmonary
emboli, CNS hemorrhage, pancytopenia, wound dehis-
cence, and colonic perforation.
Based on these intriguing preliminary studies, two
large phase III clinical trials were performed to determine
the impact of adding bevacizumab to standard chemo-
radiation with temozolomide in newly diagnosed GBM
patients. The first study was the Avastin in Glioblastoma
Trial (AVAglio), an international effort based mainly
in Europe, which enrolled 921 patients and randomly
assigned them to receive either bevacizumab (10 mg/kg
every 2 weeks) or placebo, plus standard radiotherapy
and concomitant temozolomide.91 The coprimary end-
points of the study were PFS and overall survival. After
chemoradiation was completed, patients received either
bevacizumab or placebo every 2 weeks, along with adju-
vant temozolomide (150–200 mg/m2/day) for up to six
cycles. After the completion of adjuvant temozolomide,
patients would continue with single-agent bevacizumab
(15 mg/kg every 3 weeks) or placebo until disease pro-
gression or unacceptable toxicity. The median PFS was
longer in the bevacizumab group than in the placebo
group (median 10.6  months vs 6.2  months; HR  = 064;
p < 0.001). Overall survival was not significantly different
between the groups (median 16.8 months vs 16.7 months;
HR = 0.88; p = 0.10). The overall survival rates of the bev-
acizumab and placebo groups were 72.4% and 66.3%
at 1 year (p = 0.049) and 33.9% and 30.1% at 2 years
(p = 0.24), respectively. Health-related quality of life and
performance status were maintained longer in the beva-
cizumab group; in addition, they required a lower dose
of corticosteroids. The other phase III trial was the RTOG
0825 study, which enrolled and randomized 637 patients
with newly diagnosed GBM and had design and treat-
ment groups similar to those of the AVAglio study, except
that during the adjuvant treatment phase, patients could
continue temozolomide for up to 12 cycles.92 There was
no difference between the bevacizumab and the placebo
groups in terms of overall survival (median 15.7 months
vs 16.1 months; HR = 1.13). The PFS was longer for the
bevacizumab cohort (median 10.7 months vs 7.3 months;
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
19
HR = 0.79), but was not considered significant because
it did not reach the prespecified improvement target.
During the course of the study, the bevacizumab group
showed an increased symptom burden, worse quality of
life, and a decline in neurocognitive function in compari-
son to the placebo group.
MOLECULAR OR “TARGETED”
TREATMENT
As noted above, conventional chemotherapeutic
approaches to treatment for malignant glioma are not
predicated on the biology of the malignant phenotype.
It has become apparent that the transformed pheno-
type of brain tumor cells is highly complex and results
from the dysfunction of a variety of interrelated regula-
tory pathways.93–95 The transformation process involves
amplification or overexpression of oncogenes in combi-
nation with loss or lack of expression of tumor suppres-
sor genes. Oncogenes and signal transduction molecules
that have been demonstrated to be important for glio-
magenesis include PDGF and its receptor (PDGFR),
EGF and EGFR, CDK4, mdm-2, Ras, phosphoinositol-3
kinase (PI3K), Akt, and mTOR (mammalian target of
rapamycin). Tumor suppressor genes of importance in
glial transformation include p53, retinoblastoma, p16
and p15 (i.e., INK4a, INK4b), DMBT1, and PTEN. Most
of these tumor suppressor genes function as negative
regulators of the cell cycle, whereas others are inhibitors
of important internal signal transduction pathways. The
net effect of these acquired abnormalities is dysregula-
tion of, and an imbalance between, the activity of the cell
cycle and apoptotic pathways.
Because the survival of patients with high-grade
gliomas has remained so poor using conventional che-
motherapeutic approaches, new treatment modalities
are being investigated that have a more molecular, “tar-
geted” mechanism of action, with the ability to overcome
the transformed phenotype.59,60,96–98 Advances in growth
factor and signal transduction biology are now provid-
ing the background for the development of “molecu-
lar therapeutics,” a new class of drugs that manipulate
and exploit these pathways. Molecular drugs targeting
critical signal transduction pathway effectors, such as
PDGFR, EGFR, Ras, PI3K, and mTOR, have entered clini-
cal trials in brain tumor patients.59,60,96–98 To date, numer-
ous drugs have been tested in phase I, II, and III trials,
designed to target various key receptors, signal trans-
duction proteins, and cell membrane-related proteins
such as EGFR (gefitinib, erlotinib, cetuximab), PDGFR
(imatinib), Ras (tipifarnib, lonafarnib), mTOR (temsiroli-
mus), integrins (cilengitide), and protein kinase C (enza-
staurin), as well as multikinase drugs (e.g., lapatinib)
that can target combinations of the above. Preliminary
20 2.  TREATMENT OF PRIMARY BRAIN TUMORS
results suggest only modest activity against recurrent
high-grade gliomas when used as single agents. Cur-
rent and subsequent clinical trials will investigate using
molecular drugs in combination with conventional che-
motherapeutic agents (e.g., TZM, hydroxyurea), with
other molecular drugs that target different signal trans-
duction pathways, and with irradiation.
Acknowledgments
The authors thank Shawna Huckell and Nicole Ghaffari for research
assistance. Dr. Newton was supported in part by National Cancer
Institute Grant CA 16058 and the Dardinger Neuro-Oncology Center
Endowment Fund.
References
1. Newton HB. Primary brain tumors: review of etiology, diagnosis,
and treatment. Am Fam Phys. 1994;49:787–797.
2. Preston-Martin S. Epidemiology of primary CNS neoplasms. Neu-
rol Clin. 1996;14:273–290.
3. Davis FG, McCarthy BJ. Current epidemiological trends and
surveillance issues in brain tumors. Expert Rev Anticancer Ther.
2001;1:395–401.
4.  Osborne RH, Houben MPWA, Tijssen CC, Coebergh JWW, van Duijn
CM. The genetic epidemiology of glioma. Neurol. 2001;57:1751–1755.
5. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology
of primary brain tumors: current concepts and review of the litera-
ture. Neuro-Oncol. 2002;4:278–299.
6. Hess KR, Broglio DR, Bondy ML. Adult glioma incidence trends in
the United States, 1977–2000. Cancer. 2004;101:2293–2299.
7. Rodriguez FJ, Giannini C. Diagnostic neuropathology of tumors of
the central nervous system. Handbk Clin Neurol. 2012;104:77–107.
8. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classifi-
cation of tumors of the nervous system. J Neuropathol Exp Neurol.
2002;61:215–225.
9. McLendon RE, Enterline DS, Tien RD, Thorstad WL, Bruner JM.
Tumors of central neuroepithelial origin. In: Bigner DD, McLendon
RE, Bruner JM, eds. Russell & Rubinstein’s Pathology of Tumors of the
Nervous System. Sixth Edition. Volume 1. London: Arnold; 1998;9:
307–571.
10. Li J, Sulman E, Aldape K. Molecular biology of brain tumors. Hand-
bk Clin Neurol. 2012;104:23–34.
11. Sharma A, Nand Sharma D, Kumar JP, Kishor RG. Pleomorphic
xanthoastrocytoma – a clinico-pathological review. Neurol Neuro-
chir Pol. 2011;45:379–386.
12. Matthews S, Succar P, Jelinek H, et al. Diagnosis of oligodendrogli-
oma: molecular and classical histological assessment in the twenty-
first century. Asia Pac J Clin Oncol. 2012;8:213–216.
13. Jenkinson MD, Walker C, Brodbelt AR, et al. Molecular genetics,
imaging and treatment of oligodendroglial tumours. Acta Neuro-
chir (Wien). 2010;152:1815–1825.
14. Bromberg JE, van den Bent MJ. Oligodendrogliomas: molecular
biology and treatment. Oncologist. 2009;14:155–163.
15. Eberhart CG, Burger PC. Anaplasia and grading in medulloblasto-
mas. Brain Pathol. 2003;13:376–385.
16. Lamszus K. Meningioma pathology, genetics, and biology. J Neuro-
pathol Exp Neurol. 2004;63:275–286.
17. Perry A, Gutmann DH, Reifenberger G. Molecular pathogenesis of
meningiomas. J Neuro-Oncol. 2004;70:183–202.
18. Deckert M, Engert A, Bruck W, et al. Modern concepts in the bi-
ology, diagnosis, differential diagnosis, and treatment of primary
central nervous system lymphoma. Leukemia. 2011;25:1797–1807.
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
19. Parney IF, Berger MS. Principles of brain tumor surgery. Handbk
Clin Neurol. 2012;104:187–213.
20. Dunn IF, Black PM. The neurosurgeon as local oncologist: cellular
and molecular neurosurgery in malignant glioma therapy. Neuro-
surg. 2003;52:1411–1424.
21. Choi BD, Mehta AI, Batich KA, et al. The use of motor map-
ping to aid resection of eloquent gliomas. Neurosurg Clin N Am.
2012;23:215–225.
22. Orringer DA, Golby A, Jolesz F. Neuronavigation in the surgical
management of brain tumors: current and future trends. Expert Rev
Med Devices. 2012;9:491–500.
23. Liang D, Schulder M. The role of intraoperative magnetic
resonance imaging in glioma surgery. Surg Neurol Int. 2012;3:
S320–S327.
24. Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis
of 416 patients with glioblastoma multiforme: prognosis, extent of
resection, and survival. J Neurosurg. 2001;95:190–198.
25. Bloch O, Han SJ, Cha S, et al. Impact of extent of resection for recur-
rent glioblastoma on overall survival: clinical article. J Neurosurg.
2012;117:1032–1038.
26. Caruso C, Carcaterra M, Donato V. Role of radiotherapy for high
grade glioma management. J Neurosurg Sci. 2013;57:163–169.
27. Wind JJ, Young R, Saini A, Sherman JH. The role of adjuvant radia-
tion therapy in the management of high-grade gliomas. Neurosurg
Clin N Am. 2012;23:247–258.
28. Minniti G, Goldsmith C, Brada M. Radiotherapy. Handbk Clin
Neurol. 2012;104:215–228.
29. Kortmann RD, Jeremic B, Bamberg M. Radiotherapy in the manage-
ment of low-grade gliomas. In: Petrovich Z, Brady LW, Apuzzo ML,
Bamberg M, eds. Combined Modality Therapy of Central Nervous
System Tumors. Vol. 16. Berlin: Springer; 2001:317–326.
30. Chang EL, Yi W, Allen PK, Levin VA, Sawaya RE, Maor MH. Hypo-
fractionated radiotherapy for elderly or younger low-performance
status glioblastoma patients: outcome and prognostic factors. Int J
Rad Oncol Biol Phys. 2003;56:519–528.
31. Roa W, Brasher PMA, Bauman G, et al. Abbreviated course of ra-
diation therapy in older patients with glioblastoma multiforme:
a prospective randomized clinical trial. J Clin Oncol. 2004;22:
1583–1588.
32. Selker RG, Shapiro WR, Burger P, et al. The Brain Tumor Coopera-
tive Group NIH trial 87-01: a randomized comparison of surgery,
external radiotherapy, and carmustine versus surgery, interstitial
radiotherapy boost, external radiation therapy, and carmustine.
Neurosurg. 2002;51:343–357.
33. Elaimy AL, Mackay AR, Lamoreaux WT, et al. Clinical outcomes
of gamma knife radiosurgery in the salvage treatment of patients
with recurrent high-grade glioma. World Neurosurg. 2013;80:872–
878.
34. Koga T, Saito N. Efficacy and limitations of stereotactic radiosur-
gery in the treatment of glioblastoma. Neurol Clin Chir (Tokyo).
2012;52:548–552.
35. Tsao MN, Mehta MP, Whelan TJ, et al. The American Society for
Therapeutic Radiology and Oncology (ASTRO) evidence-based
review of the role of radiosurgery for malignant glioma. Int J Rad
Oncol Biol Phys. 2005;63:47–55.
36. Souhami L, Seiferheld W, Brachman D, et al. Randomized com-
parison of stereotactic radiosurgery followed by conventional
radiotherapy with carmustine to conventional radiotherapy with
carmustine for patients with glioblastoma multiforme: report of
Radiation Therapy Oncology Group 93-05 protocol. Int J Rad Oncol
Biol Phys. 2004;60:853–860.
37. Newton HB. Chemotherapy of high-grade astrocytomas.
In: Newton HB, ed. Handbook of Brain Tumor Chemotherapy. Vol. 24.
London: Elsevier Medical Publishers-Academic Press; 2006:347–363.
38. Blakeley J, Grossman SA. Chemotherapy with cytotoxic and cyto-
static agents in brain cancer. Handbk Clin Neurol. 2012;104:229–265.
 References
39. Viaccoz A, Lekoubou A, Ducray F. Chemotherapy in low-grade
gliomas. Curr Opin Oncol. 2012;24:694–701.
40. Malkin MG. Chemotherapy of low-grade astrocytomas. In: Newton
HB, ed. Handbook of Brain Tumor Chemotherapy. Vol. 25. London:
Elsevier Medical Publishers-Academic Press; 2006:364–370.
41. Fine HA, Dear KBG, Loeffler JS, Black PM, Canellos GP. Meta-analysis
of radiation therapy with and without adjuvant chemotherapy for
malignant gliomas in adults. Cancer. 1993;71:2585–2597.
42. Steward LA, Burdett S, Souhami RL, Stenning S. Chemothera-
py in adult high-grade glioma: a systematic review and meta-
analysis of individual patient data from 12 randomised trials.
Lancet. 2002;359:1011–1018.
43. El Kamar FG, Abrey LE. Chemotherapy for primary central ner-
vous system lymphoma. In: Newton HB, ed. Handbook of Brain
Tumor Chemotherapy. Vol. 28. London: Elsevier Medical Publishers-
Academic Press; 2006:395–406.
44. Stevens MFG, Newlands ES. From triazines and triazenes to temo-
zolomide. Eur J Cancer. 1993;20A:1045–1047.
45. Newlands ES, O’Reilly SM, Glaser MG, et al. The Charing Cross
Hospital experience with temozolomide in patients with gliomas.
Eur J Cancer. 1996;2A:2236–2241.
46. Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, Brock C.
Temozolomide: a review of its discovery, chemical properties,
pre-clinical development and clinical trials. Cancer Treat Rev.
1997;23:35–61.
47. Hvizdos KM, Goa KL. Temozolomide. CNS Drugs. 1999;12:237–243.
48. Yung WKA, Prados MD, Yaya-Tur R, et al. Multicenter phase II tri-
al of temozolomide in patients with anaplastic astrocytoma or ana-
plastic oligoastrocytoma at first relapse. J Clin Oncol. 1999;17:2762–
2771.
49. Yung WKA, Albright RE, Olson J, et al. A phase II study of temo-
zolomide vs. procarbazine in patients with glioblastoma multi-
forme at first relapse. Br J Cancer. 2000;83:588–593.
50. Stupp R, Dietrich PY, Kraljevic SO, et al. Promising survival for
patients with newly diagnosed glioblastoma treated with concomi-
tant radiation plus temozolomide followed by adjuvant temozolo-
mide. J Clin Oncol. 2002;20:1375–1382.
51. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. New
Engl J Med. 2005;352:987–996.
52. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with
concomitant and adjuvant temozolomide versus radiothera-
py alone on survival in glioblastoma in a randomized phase III
study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol.
2009;10:459–466.
53. Strik HM, Marosi C, Kaina B, Neyns B. Temozolomide dosing regi-
mens for glioma patients. Curr Neurol Neurosci Rep. 2012;12:286–293.
54. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide
for newly diagnosed glioblastoma: a randomized phase III clinical
trial. J Clin Oncol. 2013;31:4085–4091.
55. Cavallaro U, Christofori G. Molecular mechanisms of tumor angio-
genesis and tumor progression. J Neuro-Oncol. 2000;50:63–70.
56. Webb CP, Vande Woude GF. Genes that regulate metastasis and
angiogenesis. J Neuro-Oncol. 2000;50:71–87.
57. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropath Exp
Neurol. 1999;58:313–320.
58. Hardee ME, Zagzag D. Mechanisms of glioma-associated neovas-
cularization. Am J Pathol. 2012;181:1126–1141.
59. Newton HB. Molecular neuro-oncology and the development of
“targeted” therapeutic strategies for brain tumors. Part 2 – PI3K/
Akt/PTEN, mTOR, SHH/PTCH, and angiogenesis. Expert Rev An-
ticancer Ther. 2004;4:105–128.
60. Newton HB. Molecular neuro-oncology and the development of
“targeted” therapeutic strategies for brain tumors. Part 1 – growth
factor and ras signaling pathways. Expert Rev Anticancer Ther.
2003;3:595–614.
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
21
61. Jensen RL. Growth factor-mediated angiogenesis in the ma-
lignant progression of glial tumors: a review. Surg Neurol.
1998;49:189–196.
62. Dunn IF, Heese O, Black PM. Growth factors in glioma angio-
genesis: FGFs, PDGF, EGF, and TGFs. J Neuro-Oncol. 2000;50:
121–137.
63. Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-
inducible factor 1α in brain tumors. Association with angiogenesis,
invasion, and progression. Cancer. 2000;88:2606–2618.
64. Jiang BH, Jiang G, Zheng JZ, et al. Phosphatidylinositol 3-kinase
signaling controls levels of hypoxia-inducible factor 1. Cell Growth
Differ. 2001;12:363–369.
65. Wen S, Stolarov J, Myers MP, et al. PTEN controls tumor-induced
angiogenesis. Proc Natl Acad Sci USA. 2001;98:4622–4627.
66. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth
factor pathway in tumor growth and angiogenesis. J Clin Oncol.
2005;23:1011–1027.
67. Levine AM, Tulpule A, Quinn DI, et al. Phase I study of antisense
oligonucleotide against vascular endothelial growth factor: de-
crease in plasma vascular endothelial growth factor with potential
clinical efficacy. J Clin Oncol. 2006;24:1712–1719.
68. Wachsberger PR, Burd R, Cardi C, et al. VEGF trap in combination
with radiotherapy improves tumor control in U87 glioblastoma.
Int J Rad Oncol Biol Phys. 2007;67:1526–1537.
69. Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D.
Vascular endothelial growth factor (VEGF) as a target of bevaci-
zumab in cancer: from the biology to the clinic. Curr Med Chem.
2006;13:1845–1857.
70. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the
treatment of solid malignancies. Clin Ther. 2006;28:1779–1802.
71. Kunkel P, Ulbricht U, Bohlen P, et al. Inhibition of intracranial gli-
oma angiogenesis and growth in vivo by systemic treatment with
a monoclonal antibody against vascular endothelial growth factor
receptor-2. Cancer Res. 2001;61:6624–6628.
72. Stefanik DF, Fellows WK, Rizkalla LR, et al. Monoclonal antibodies
to vascular endothelial growth factor (VEGF) and the VEGF recep-
tor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft.
J Neuro-Oncol. 2001;55:91–100.
73. Newton HB. Overview of angiogenesis and the use of bevacizum-
ab in patients with malignant gliomas. Curr Signal Transduct Ther.
2013;8:25–35.
74. Stark-Vance V. Bevacizumab and CPT-11 in the treatment of re-
lapsed malignant glioma. In: World Federation of Neuro-Oncology
Meeting. 2005:91.
75. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of
bevacizumab and irinotecan in recurrent malignant glioma. Clin
Cancer Res. 2007;13:1253–1259.
76. Goli KJ, Desjardins A, Herndon JE, et al. Phase II trial of bevaci-
zumab and irinotecan in the treatment of malignant gliomas (ab-
stract). J Clin Oncol (Suppl). 2007;18S:75s.
77. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab
plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol.
2007;25:4722–4729.
78. Kang T, Jin T, Elinzano H, Peereboom D. Irinotecan and bevaci-
zumab in progressive primary brain tumors, an evaluation of ef-
ficacy and safety. J Neuro-Oncol. 2008;89:113–118.
79. Gilbert MR, Wang M, Aldape K, Lassman A, Sorensen AG,
Mikkelson T, et al. RTOG 0625: a phase II study of bevacizumab
and irinotecan in recurrent glioblastoma (GBM) (abstract). J Clin
Oncol (Suppl). 2009;27:89s.
80. Ali SA, McHayleh WM, Ahmad A, Sehgal R, Braffet M, Rahman M,
et al. Bevacizumab and irinotecan in glioblastoma multiforme:
a series of 13 cases. J Neurosurg. 2008;109:268–272.
81. Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizum-
ab and irinotecan for recurrent high-grade glial tumors. Cancer.
2008;112:2267–2273.
22 2.  TREATMENT OF PRIMARY BRAIN TUMORS
82. Poulsen HS, Grunnet K, Sorensen M, et al. Bevacizumab plus irino-
tecan in the treatment of patients with progressive recurrent malig-
nant brain tumours. Acta Oncol. 2009;48:52–58.
83. Desjardins A, Reardon DA, Herndon JE, et al. Bevacizumab plus
irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Can-
cer Res. 2008;14:7068–7073.
84. Gordon MS, Cunningham D. Managing patients treated with beva-
cizumab combination therapy. Oncology. 2005;69:25–33.
85. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and
in combination with irinotecan in recurrent glioblastoma. J Clin
Oncol. 2009;27:4733–4740.
86. Vredenburgh JJ, Cloughesy T, Samant M, et al. Corticosteroid use
in patients with glioblastoma at first or second relapse treated with
bevacizumab in the BRAIN study. Oncology. 2010;15:1329–1334.
87. Lai A, Filka E, McGibbon B, Nghiemphu PL, et al. Phase II pilot
study of bevacizumab in combination with temozolomide and
regional radiation therapy for up-front treatment of patients with
newly diagnosed glioblastoma mutiforme: Interim analysis of safe-
ty and tolerability. Int J Rad Oncol Biol Phys. 2008;71:1372–1380.
88. Narayana A, Golfinos JG, Fischer I, et al. Feasibility of using beva-
cizumab with radiation therapy and temozolomide in newly diag-
nosed high-grade glioma. Int J Rad Oncol Biol Phys. 2008;72:383–389.
89. Vredenburgh JJ, Desjardins A, Reardon DA, et al. The addition of
bevacizumab to standard radiation therapy and temozolomide fol-
lowed by bevacizumab, temozolomide, and irinotecan for newly
diagnosed glioblastoma. Clin Cancer Res. 2011;17:4119–4124.
I.  OVERVIEW OF NEURO-ONCOLOGICAL DISORDERS
90. Vredenburgh JJ, Adejardins A, Kirkpatrick JP, et al. Addition of
bevacizumab to standard radiation therapy and daily temozolo-
mide is associated with minimal toxicity in newly diagnosed
glioblastoma multiforme. Int J Rad Oncol Biol Phys. 2012;82:
58–66.
91. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-
temozolomide for newly diagnosed glioblastoma. New Engl J Med.
2014;370:709–722.
92. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of
bevacizumab for newly diagnosed glioblastoma. New Engl J Med.
2014;370:699–708.
93. Marumoto T, Saya H. Molecular biology of glioma. Adv Exp Med
Biol. 2012;746:2–11.
94. Li J, Sulman E, Aldape K. Molecular biology of brain tumors. Hand-
bk Clin Neurol. 2012;104:23–34.
95. Westphal M, Lamszus K. The neurobiology of gliomas: from cell
biology to the development of therapeutic approaches. Nat Rev
Neurosci. 2011;12:495–508.
96. Newton HB. Molecular neuro-oncology and the development of
“targeted” therapeutic strategies for brain tumors. Part 5 – apoptosis
and cell cycle. Expert Rev Anticancer Ther. 2005;5:355–378.
97. Sathornsumetee S, Rich JN. Molecularly targeted therapy in neuro-
oncology. Handbk Clin Neurol. 2012;104:255–278.
98. Hamza MA, Gilbert M. Targeted therapy in gliomas. Curr Oncol
Rep. 2014;16(4):379.