ASTROCYTOMA

Practice Essentials
Astrocytomas are CNS neoplasms in which the predominant cell type is derived from an
immortalized astrocyte.
[1]
Survival correlates most highly with the intrinsic properties of
the astrocytoma and typically ranges from approximately 10 years from the time of
diagnosis for patients with pilocytic astrocytomas to less than 1 year for patients with
glioblastoma.
Essential update: Chemotherapy following radiation may improve survival in low-
grade gliomas
In an NIH-supported, randomized, controlled study of 251 patients with low-grade
gliomas who were aged 40 years and older or who had incomplete surgical removal of
their tumor, those treated with a chemotherapy regimen following completion of
radiation therapy had significantly improved survival compared with those treated with
radiation therapy alone.
[2]

Half of the patients received no further treatment after radiation therapy, while the other
half also received 6 cycles of chemotherapy (procarbazine, CCNU, and vincristine). At a
median follow-up of 12 years, median overall survival was 13.3 years in the
chemotherapy group and 7.8 years in the radiation-only group.
[2]

Signs and symptoms
Neurologic symptoms from astrocytoma development depend foremost on the site and
extent of tumor growth in the CNS but may include any of the following:
Altered mental status
Cognitive impairment
Headaches
Nausea and vomiting
Visual disturbances
Motor impairment
Seizures
Sensory anomalies
Ataxia
Astrocytomas of the spinal cord or brainstem are less common and present as
motor/sensory or cranial nerve deficits referable to the tumor's location.
On physical examination, patients may demonstrate signs of increased ICP or localizing
and lateralizing signs such as the following:
Cranial nerve palsies
Hemiparesis
Sensory levels
Alteration of deep tendon reflexes (DTRs)
Pathologic reflexes (eg, Hoffman sign, Babinski sign)
See Clinical Presentation for more detail.
Diagnosis
No laboratory studies are diagnostic of astrocytoma, but the following baseline
laboratory studies may be obtained for general metabolic surveillance and preoperative
assessment:
Basic metabolic profile
CBC
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
MRI
MRI is considered the criterion standard imaging study
Astrocytomas are generally isointense on T1-weighted images and hyperintense on
T2-weighted images
While low-grade astrocytomas uncommonly enhance on MRI, most anaplastic
astrocytomas enhance with paramagnetic contrast agents
The possibility of metastatic disease must be considered in cases in which a cortically
based enhancing mass is discovered, particularly if multiple lesions are identified
High-resolution MRI is now often used to provide intraoperative image guidance
CT scanning
A CT scan may be useful in the acute setting or when MRI is contraindicated
On CT, low-grade astrocytomas appear as poorly defined, homogeneous, low-density
masses without contrast enhancement; however, slight enhancement, calcification,
and cystic changes may be evident early in the course of the disease
Systemic imaging, generally consisting of a contrast-enhanced CT scan of the chest,
abdomen, and pelvis, may be warranted to evaluate for the possibility of an alternate
primary lesion
Anaplastic astrocytomas may appear as low-density lesions or inhomogeneous
lesions, with areas of both high and low density within the same lesion; unlike low-
grade lesions, partial contrast enhancement is common
Angiography
May be used to rule out vascular malformations and to evaluate tumor blood supply
A normal angiographic pattern or a pattern consistent with an avascular mass that
displaces normal vessels is usually observed with both low-grade and high-grade
lesions
In rare instances, a tumor blush may be observed with high-grade lesions
Radionuclide scans
PET, SPECT, or technetium-based imaging can permit study of tumor metabolism and
brain function
PET and SPECT may be used to distinguish a solid tumor from edema, to differentiate
tumor recurrence from radiation necrosis, and to localize structures
Metabolic activity of a lesion can be used to determine tumor grade; hypermetabolic
lesions often correspond to higher-grade tumors
Other studies
EEG may be used to evaluate and monitor epileptiform activity
ECG and chest radiographs are indicated to evaluate operative risk
CSF studies may be used to rule out other diagnoses (eg, metastasis, lymphoma,
medulloblastoma)
See Workup for more detail.
Management
There is no accepted standard of treatment for low-grade or anaplastic astrocytoma.
Treatment decisions are generally best made through a team approach, including input
from the involved neurosurgeon, radiation oncologist, and medical oncologist or
neurologist.
Typically, anaplastic astrocytomas are treated with the following:
Surgery
Radiotherapy
Adjuvant temozolomide
Some practitioners add concomitant temozolomide
[3, 4]

Some smaller survival benefit has been shown with adjuvant carmustine
[5]

Treatment of low-grade astrocytomas remains more controversial. The role of maximal
surgical resection, timing of radiotherapy, and the role, timing, and appropriate agents of
chemotherapy are not clear.
Surgical care
Stereotactic biopsy is a safe and simple method for establishing a tissue diagnosis
Tumor resection can be performed safely and is generally undertaken with the intent to
cause the least possible neurologic injury to the patient
Surgical resection provides improved survival advantage and histologic diagnosis of
the tumor rather than offering a cure
Total resection of an astrocytoma is often impossible because the tumors often invade
eloquent regions of the brain and exhibit tumor infiltration that is only detectable on a
microscopic scale
Diversion of CSF by external ventricular drain (EVD) or ventriculoperitoneal shunt
(VPS) may be required to decrease ICP
Symptomatic therapy
Patients with an astrocytoma and a history of seizures should receive anticonvulsant
therapy, with monitoring of the serum drug concentration; levetiracetam (Keppra) is
often used
Prophylactic use of anticonvulsants in astrocytoma patients with no prior history of
seizures has been reported but remains controversial
The use of corticosteroids, such as dexamethasone, yields rapid improvement in most
patients secondary to a reduction of tumor mass effect; patients receiving
corticosteroids should have concurrent prophylaxis for gastrointestinal ulcers
Brainstem gliomas
Treatment and prognosis for brainstem gliomas typically depends on whether the tumor
is diffuse or focal. Treatment of diffuse brainstem gliomas is as follows:
No benefit of surgical resection has been shown
Corticosteroids may provide temporary benefit by reduction of edema
Irradiation and chemotherapy are sometimes used, but neither has been shown to
cure or prolong survival, and radiation necrosis and chemotherapy side effects can be
significant
Treatment of focal brainstem gliomas is as follows:
Surgery is often the primary treatment, although the decision to operate, the surgical
approach, and the extent of resection depend on location, patient factors, and the
surgeon's judgment
Obstructive hydrocephalus is common and usually treated by a separate procedure,
either endoscopic third ventriculostomy or shunt placement
[6]


BACKGROUND
Astrocytomas are CNS neoplasms in which the predominant cell type is derived from an
immortalized astrocyte.
[1]
Two classes of astrocytic tumors are recognizedthose with
narrow zones of infiltration (eg, pilocytic astrocytoma, subependymal giant cell
astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of
infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Members
of the latter group share various features, including the ability to arise at any site in the
CNS, with a preference for the cerebral hemispheres; clinical presentation usually in
adults; heterogeneous histopathological properties and biological behavior; diffuse
infiltration of contiguous and distant CNS structures, regardless of histological stage;
and an intrinsic tendency to progress to more advanced grades. See the image below.
Gross specimen of a low-grade astrocytoma.
Numerous grading schemes based on histopathologic characteristics have been
devised, including the Bailey and Cushing grading system, Kernohan grades I-IV, World
Health Organization (WHO) grades I-IV, and St. Anne/Mayo grades 1-4. Regions of a
tumor demonstrating the greatest degree of anaplasia are used to determine the
histologic grade of the tumor. This practice is based on the assumption that the areas of
greatest anaplasia determine disease progression.
This article focuses on the widely accepted WHO grading scheme that relies on
assessments of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and
necrosis.
[7]
WHO grade I corresponds to pilocytic astrocytoma, WHO grade II
corresponds to low-grade (diffuse) astrocytoma, WHO grade III corresponds to
anaplastic astrocytoma, and WHO grade IV corresponds to glioblastoma multiforme
(GBM). This article is confined to low-grade and anaplastic astrocytomas. GBM and
pilocytic astrocytoma are not discussed in this article
Pathophysiology
Regional effects of astrocytomas include compression, invasion, and destruction of
brain parenchyma. Arterial and venous hypoxia, competition for nutrients, release of
metabolic end products (eg, free radicals, altered electrolytes, neurotransmitters), and
release and recruitment of cellular mediators (eg, cytokines) disrupt normal
parenchymal function. Elevated intracranial pressure (ICP) attributable to direct mass
effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume may
mediate secondary clinical sequelae. Neurological signs and symptoms attributable to
astrocytomas result from perturbation of CNS function. Focal neurological deficits (eg,
weakness, paralysis, sensory deficits, cranial nerve palsies) and seizures of various
characteristics may permit localization of lesions.
[8]

Infiltrating low-grade astrocytomas grow slowly compared to their malignant
counterparts. Doubling time for low-grade astrocytomas is estimated at 4 times that of
anaplastic astrocytomas. Several years often intervene between the initial symptoms
and the establishment of a diagnosis of low-grade astrocytoma. One recent series
estimated the interval to be approximately 3.5 years. The clinical course is marked by a
gradual deterioration in half of cases, a stepwise decline in one third of cases, and a
sudden deterioration in 15% of cases. Seizures, often generalized, are the initial
presenting symptom in about half of patients with low-grade astrocytoma.
For patients with anaplastic astrocytomas,
[9]
the growth rate and interval between onset
of symptoms and diagnosis is intermediate between low-grade astrocytomas and
glioblastomas. Although highly variable, a mean interval of approximately 1.5-2 years
between onset of symptoms and diagnosis is frequently reported. Compared to low-
grade lesions, seizures are less common among patients with anaplastic astrocytomas.
Initial presenting symptoms most commonly are headache, depressed mental status,
and focal neurological deficits
Frequency
United States
The annual incidence of glioma in the United States is 5.4 cases per 100,000
population.
International
Incidence differences are not significant between the United States and other countries.
Mortality/Morbidity
Morbidity and mortality, as defined by the length of a patient's history and the odds of
recurrence-free survival, are correlated most highly with the intrinsic properties of the
astrocytoma in question. Typical ranges of survival are approximately 10 years from the
time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for
patients with low-grade diffuse astrocytomas (WHO grade II),
[10]
2-5 years for those with
anaplastic astrocytomas (WHO grade III), and less than 1 year for patients with
glioblastoma (WHO grade IV).
Race
Although genetic determinants are recognized in astrocytoma development and
progression, astrocytomas do not differ intrinsically in incidence or behavior among
racial groups. Demographic and sociological factors, such as population, age, ethnic
attitude toward disease, and access to care, have been reported to influence measured
distributions.
Sex
No clear sex predominance has been identified in the development of pilocytic
astrocytomas. A slight male predominance, with a male-to-female ratio of 1.18:1 for
development of low-grade astrocytomas, has been reported. A more significant male
predominance, with a male-to-female ratio of 1.87:1 for the development of anaplastic
astrocytomas, has been identified.
Age
Most cases of pilocytic astrocytoma present in the first 2 decades of life. In contrast, the
peak incidence of low-grade astrocytomas, representing 25% of all cases in adults,
occurs in people aged 30-40 years. Ten percent of low-grade astrocytomas occur in
people younger than 20 years; 60% of low-grade astrocytomas occur in people aged
20-45 years; and 30% of low-grade astrocytomas occur in people older than 45 years.
The mean age of patients undergoing a biopsy of anaplastic astrocytoma is 41 years.
Epidemiology
Sex
No clear sex predominance has been identified in the development of pilocytic
astrocytomas. A slight male predominance, with a male-to-female ratio of 1.18:1 for
development of low-grade astrocytomas, has been reported. A more significant male
predominance, with a male-to-female ratio of 1.87:1 for the development of anaplastic
astrocytomas, has been identified

CLINICAL PRESENTATION
History
The type of neurological symptoms that result from astrocytoma development depends
foremost on the site and extent of tumor growth in the CNS. Reports of altered mental
status, cognitive impairment, headaches, visual disturbances, motor impairment,
seizures, sensory anomalies, or ataxia in the patient's history should alert the clinician to
the presence of a neurological disorder and should indicate a requirement for further
studies. In this event, radiographic imaging, such as CT scan and MRI (with and without
contrast), is indicated. Astrocytomas of the spinal cord or brainstem are less common
and present with motor/sensory or cranial nerve deficits referable to the tumor's
location.
Physical
A detailed neurological examination is required for the proper evaluation of any patient
with an astrocytoma. Because these tumors may affect any part of the CNS, including
the spinal cord, and may spread to distant regions of the CNS, a thorough physical
examination referable to the entire neuraxis is necessary to define the location and
extent of disease.
Special attention should be paid to signs of increased ICP, such as headache, nausea
and vomiting, decreased alertness, cognitive impairment, papilledema, or ataxia, to
determine the likelihood of mass effect, hydrocephalus, and herniation risk. Localizing
and lateralizing signs, including cranial nerve palsies, hemiparesis, sensory levels,
alteration of deep tendon reflexes (DTRs), and the presence of pathological reflexes
(eg, Hoffman and Babinski signs), should be noted. Once neurological abnormalities are
identified, imaging studies should be sought for further evaluation
Causes
The etiology of diffuse astrocytomas has been the subject of analytic epidemiological
studies that have yielded associations with various disorders and exposures.
[11]
With the
exception of therapeutic irradiation
[12]
and, perhaps, nitroso compounds (eg,
nitrosourea), the identification of specific causal environmental exposures or agents has
been unsuccessful. Although some concern has been raised regarding cell phone use
as a potential risk factor for development of gliomas, the largest studies have not
supported this.
[13, 14, 15, 16, 17]

Children receiving prophylactic irradiation for acute lymphatic leukemia (ALL), for
example, have a 22-fold increased risk of developing CNS neoplasms in WHO grade II,
III, and IV astrocytomas, with an interval for onset of 5-10 years. Furthermore,
irradiation of pituitary adenomas has been demonstrated to carry a 16-fold increased
risk of glioma formation.
[18]

Evidence exists for genetic susceptibility to glioma development. For example, familial
clustering of astrocytomas is well described in inherited neoplastic syndromes, such as
Turcot syndrome, neurofibromatosis type 1 (NF1) syndrome, and p53 germ line
mutations (eg, Li-Fraumeni syndrome).
Biological investigation has implicated that mutations in specific molecular pathways,
such as the p53-MDM2-p21 and p16-p15-CDK4-CDK6-RB pathways, are associated
with astrocytoma development and progression. In addition, inherited elements of the
immune response known as human leukocyte antigens (HLA) have been both positively
and negatively associated with an increased risk for the development of glioblastoma
multiforme. Two-thirds of low-grade astrocytomas have p53 mutations.
[19]

Recently, attempts have been made to determine prognosis and response to various
treatment modalities based on the individual pattern of genetic changes in a particular
patient. For example, patients with oligodendrogliomas that exhibit chromosomal
changes at band 1p19q are known to have improved responses to the procarbazine,
CCNU, vincristine (PCV) regimen of chemotherapy. Efforts are underway to identify
similar unique susceptibilities associated with other commonly altered genes and
proteins in astrocytomas. Other groups are working on developing models that will allow
for a more accurate assessment of prognosis based on a combination of molecular
profiling of the tumors and clinical characteristics of the patient.
[20]


WORKUP
Laboratory Studies
No laboratory studies are diagnostic of astrocytoma. Baseline laboratory studies,
including basic metabolic profile, complete blood cell count (CBC), prothrombin time
(PT), and activated partial thromboplastin time (aPTT), may be obtained for general
metabolic surveillance and preoperative assessment.
Imaging Studies
CT scans and MRI (with and without contrast) are helpful in the diagnosis, grading, and
pathophysiological evaluation of astrocytomas. MRI is considered the criterion standard,
but a CT scan may be useful in the acute setting or when MRI is contraindicated.
On a CT scan, low-grade astrocytomas appear as poorly defined, homogeneous, low-
density masses without contrast enhancement. However, slight enhancement,
calcification, and cystic changes may be evident early in the course of the disease. In
cases where a cortically based enhancing mass is discovered, particularly in cases
where multiple lesions are identified, the possibility of metastatic disease must be
considered. Systemic imaging, generally consisting of a contrast-enhanced CT scan of
the chest, abdomen, and pelvis, may be warranted to evaluate for the possibility of an
alternate primary lesion.
Similarly, anaplastic astrocytomas may appear as low-density lesions or
inhomogeneous lesions, with areas of both high and low density within the same lesion.
Unlike low-grade lesions, partial contrast enhancement is common.
Astrocytomas are generally isointense on T1-weighted images and hyperintense on T2-
weighted images. While low-grade astrocytomas uncommonly enhance on MRI, most
anaplastic astrocytomas enhance with paramagnetic contrast agents. New methods are
being developed to assess tumor vascularity by MRI, including techniques such as
arterial-spin labeling (ASL) and dynamic contrast-enhanced MRI.
Angiography may be used to rule out vascular malformations and to evaluate tumor
blood supply. A normal angiographic pattern or a pattern consistent with an avascular
mass that displaces normal vessels is usually observed with both low-grade and high-
grade lesions. In rare instances, a tumor blush may be observed with high-grade
lesions.
Imaging has also taken a larger role in the operating room, as many procedures are
now performed with intraoperative image guidance based upon high-resolution MRIs. In
addition, intraoperative MRI and CT scans are being tested for utility in guiding the
extent of resection and presence of residual tumor during the surgical procedure.
Ultimately, the boundaries of infiltrating tumors extend far beyond what can be seen by
imaging studies. New methods of tumor imaging are being developed to specifically tag
or label tumor cells so they may be visualized in the operating room. Such methods
include pretreatment of the patient with dyes or tumor-specific proteins tagged with
fluorescent molecules.
Other Tests
Because seizure activity is often associated with astrocytomas, EEG may be employed
to evaluate and monitor epileptiform activity.
Radionuclide scans, such as positron emission tomography (PET), single-photon
emission tomography (SPECT), and technetium-based imaging, can permit study of
tumor metabolism and brain function. PET and SPECT may be used to distinguish a
solid tumor from edema, to differentiate tumor recurrence from radiation necrosis, and
to localize structures.
Metabolic activity determined by radionuclide scans can be used to determine the grade
of a lesion. Hypermetabolic lesions often correspond to higher-grade tumors.
ECG and chest radiographs are indicated to evaluate operative risk.
Procedures
A lumbar puncture (LP) in patients with cerebral astrocytomas should be approached
with extreme caution because of the risk of downward cerebral herniation secondary to
elevated ICP. Although CSF studies are not employed in the diagnosis of astrocytomas,
they may be employed to rule out other possible diagnoses, such as metastasis,
lymphoma, or medulloblastoma.
Histologic Findings
Four histological variants of low-grade astrocytomas are recognizedprotoplasmic,
gemistocytic, fibrillary, and mixed.
[21]

1. Protoplasmic astrocytomas are generally cortically based, with cells containing
prominent cytoplasm. Protoplasmic astrocytomas constitute approximately 28%
of infiltrating astrocytomas.
2. Gemistocytic astrocytomas are generally found in the cerebral hemispheres in
adults and are composed of large round cells with eosinophilic cytoplasm and
eccentric cytoplasm. Gemistocytic astrocytomas constitute 5-10% of hemispheric
gliomas.
3. Fibrillary astrocytomas, the most frequent histological variant, resemble cells
from the cerebral white matter and are composed of small, oval, well-
differentiated cells. The tumors are identified by a mild increase in cellularity and
fibrillary background. Markers for glial fibrillary acidic protein (GFAP) are used to
identify fibrillary astrocytomas.
4. Compared to low-grade lesions, anaplastic astrocytomas show a marked
tendency for regional or diffuse hypercellularity. Furthermore, anaplastic
astrocytomas show increased anaplasia, demonstrated by increased nuclear
complexity, the presence of mitoses, increased cytoplasmic variability, and
increased endothelial cell proliferation.
Staging
Staging is not performed or described for patients with astrocytoma. The histologic
grade of the tumor is of primary importance when determining prognosis. Unlike other
systemic tumors, distant or extracranial metastasis of astrocytomas is exceedingly rare.
Clinical decline and tumor-associated morbidity and mortality are almost always
associated with local mass effects on the brain by a locally recurrent intracranial tumor.

TREATMENT
Medical Care
Generally, care of patients with brain tumors is primarily directed by a neurologist or
specialist in neurooncology. There is no accepted standard of treatment for low-grade or
anaplastic astrocytoma.
A study by Ishkanian et al found that adjuvant radiotherapy for pilocytic astrocytoma
significantly prolonged progression-free survival (PFS) at both 5 years and 10 years
compared with observation alone. However, the overall survival was equivalent.
[22]

Decisions on operative intervention and the use of chemotherapy and radiation therapy
are generally best made by a team approach, including input from the involved
neurosurgeon, radiation oncologist, and medical oncologist or neurologist.
Typically, anaplastic astrocytomas are treated with surgery, radiotherapy, and adjuvant
temozolomide. Some practitioners add concomitant temozolomide, though no data
from controlled trials exist to support concomitant temozolomide.
[3, 4]

Anaplastic astrocytomas are usually more responsive to chemotherapy than
glioblastomas.
[23, 24]
For recurrent anaplastic astrocytomas previously treated with
nitrosoureas, temozolomide showed a 35% response rate, and compared to therapies
with lower response rates, temozolomide provided an increased 6-month survival rate
(46% vs 31%).
[25, 26]
Some smaller survival benefit has been shown with adjuvant
carmustine.
[5]

Treatment of low-grade astrocytomas remains more controversial. The role of maximal
surgical resection, timing of radiotherapy, and the role, timing, and appropriate agents
of chemotherapy are not clear. The controversy due to a lack of strong data is
compounded by the relatively young age of the patients, the relatively indolent natural
history of low-grade astrocytomas, and the morbidity associated with these
interventions.
[27, 28]

Patients with an astrocytoma and a history of seizures should receive anticonvulsant
therapy with monitoring of the drug concentration in the blood stream. The use of
anticonvulsants prophylactically in astrocytoma patients with no prior history of
seizures has been reported but remains controversial.
The use of corticosteroids, such as dexamethasone, yields rapid improvement in most
patients secondary to a reduction of tumor mass effect. Concurrent prophylaxis for
gastrointestinal ulcers should be prescribed with corticosteroid administration.
Brainstem gliomas: Brainstem tumors account for 10-20%
[29]
of all CNS tumors in the
pediatric population, typically diagnosed between ages 7-9.
[30, 31]
Though many
classification schemes exist, treatment and prognosis for brainstem gliomas typically
depends on whether the tumor is diffuse or focal.
Diffuse brainstem gliomas make up 58-75%
[32]
of all brainstem tumors, typically arise in
the pons, and are noncircumscribed on MRI. They are often malignant fibrillary
astrocytomas (WHO grade III or IV), which infiltrate along white matter tracts into the
midbrain and thalamus and have a rapidly progressive and fatal course.
o Clinical presentation of these tumors often involves ataxia, cerebellar signs, and long
tract signs.
[33]
When clinical and radiographic evidence suggests diffuse brainstem
glioma, biopsy is of limited use as tumor histology does not frequently alter
treatment.
[32, 34, 35, 36, 37, 38, 39, 40]

o No benefit of surgical resection has been shown, largely due to the eloquence of the
region and diffuse and aggressive nature of the tumor.
[33, 41]
Corticosteroids may
provide temporary benefit by reduction of edema. Irradiation has been shown to
provide temporary clinical improvement and is sometimes employed, but a large
phase III trial showed no benefit.
[42]
Even with radiation therapy, 1-year survival has
been shown to be 35-46%, and 3-year survival 11-17%.
[43, 44]
Chemotherapy is also
sometimes used.
[45]
No treatment, however, has been shown to cure or prolong
survival in these patients, and radiation necrosis and chemotherapy side effects can
be significant. Convection-enhanced delivery of chemotherapy offers one potential
avenue for improving the prognosis of these patients, and studies are ongoing.
Focal brainstem gliomas are usually WHO grade I or II, well-circumscribed on MRI with
variable contrast enhancement, are more often found in the medulla and midbrain and
have a much better prognosis than diffuse brainstem gliomas. Surgery is often the
primary treatment for focal brainstem gliomas as well as dorsal exophytic brainstem
gliomas, though the decision to operate, surgical approach, and extent of resection
depend on location, patient factors, and the surgeon's judgment. Obstructive
hydrocephalus is common, usually treated by a separate procedure, either endoscopic
third ventriculostomy or shunt placement.
[6]

In a study of 39 children (median age, 10 years) with low-grade glioma, treatment with
intensity-modulated radiotherapy (IMRT) after incomplete resection or disease
progression was found to provide local control rates comparable to those provided by
2-dimensional and 3-dimensional radiotherapy. The 8-year progression-free and
overall survival rates with IMRT were 78.2% and 93.7%, respectively.
[46, 47]
The
researchers used three approaches to identify the target area for IMRT: The first
method (n=19) was to delineate the gross tumor volume (GTV) and add a 1-cm margin
to create the clinical target volume. In the second method (n=6), a 0.5-cm margin was
added around the GTV to create the clinical target volume. For both methods, the
prescribed GTV dose was the same as the clinical treatment volume: a median dose of
50.4 Gy.Method 3 (n=14) was dose painting: the GTV was delineated and a second
target volume was created by adding 1 cm to the GTV. The second target volume was
treated with a lower radiation dose than the GTV (median, 41.4 Gy versus 50.4 Gy).
Multivariate analysis showed no difference in progression according to the method of
target delineation, suggesting that a 1-cm margin may not be necessary.
[46, 47]

Surgical Care
The roles of surgery in the patient with astrocytoma are (1) to remove or debulk the
tumor and (2) to provide tissue for histological diagnosis, permitting tailoring of adjuvant
therapy and assessment of prognosis.
[48]
A stereotactic biopsy is a safe and simple
method for establishing a tissue diagnosis. The use of stereotactic biopsy can be limited
by sampling error and the risk of biopsy-induced intracerebral hemorrhage. Diversion of
CSF by external ventricular drain (EVD) or ventriculoperitoneal shunt (VPS) may be
required to decrease ICP as part of nonoperative management or prior to definitive
surgical therapy if hydrocephalus is present.
Total resection of astrocytoma is often impossible because the tumors often invade into
adjacent regions of the brain and exhibit tumor infiltration that is only detectable on a
microscopic scale. Therefore, surgical resection provides for improved survival
advantage and histological diagnosis of the tumor rather than offering a cure. However,
craniotomy for tumor resection can be performed safely and is generally undertaken
with the intent to cause the least possible neurological injury to the patient. Complete
resection (>98% based on volumetric MRI) has been shown to improve median survival
compared with subtotal resection (13 vs 8.8 mo).
[49]

Consultations
A neurologist should be consulted to document a patient's detailed neurological
examination. This establishes a baseline and partly assesses the possibility of occult
disease. Employing multiple modalities, the neurologist must correlate symptomatology
with anatomic and functional imaging. This physician also may manage antiepileptic
medication for patients manifesting seizures.
A neurosurgeon should be consulted to assess the risks and benefits of surgical
resection, stereotactic biopsy, stereotactic radiosurgery, and CSF diversion.
A neurooncologist may be consulted to help coordinate a comprehensive therapeutic
plan. Once a histological diagnosis is determined, the neurooncologist should be
consulted to provide comprehensive adjunctive therapy, including the use of
chemotherapy and radiation.
Activity
No broad restrictions on activity are prescribed, other than those dictated by the nature
and the extent of neurological symptoms and disability.
Seizures, if uncontrolled, may preclude driving.
Physical and occupational therapy may be required for recovery of full or partial
function.

MEDICATION
Medication Summary
No specific drug treatment exists for low-grade glioma. Certain conditions (eg, low-
grade astrocytoma) typically require treatment. For seizures, the patient is usually
started on levetiracetam (Keppra), phenytoin (Dilantin), or carbamazepine (Tegretol).
Levetiracetam is often used because it lacks the effects on the P450 system seen with
phenytoin and carbamazepine, which can interfere with antineoplastic therapy. Steroid
therapy, usually combined with gastroprotectant, is initiated for vasogenic edema
around tumor.
Anticonvulsants
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure
activity.
View full drug information
Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for
primary generalized tonic-clonic seizures. Mechanism of action is unknown.
View full drug information
Phenytoin (Dilantin)

Effective in partial and generalized tonic-clonic seizures. Blocks sodium channel and
prevents repetitive firing of action potentials.
View full drug information
Carbamazepine (Tegretol)

Similar to phenytoin. Effective in partial and generalized tonic-clonic seizures. Blocks
sodium channel and prevents repetitive firing of action potentials.
Corticosteroids
Class Summary
These drugs reduce edema around the tumor, frequently leading to symptomatic and
objective improvement.
View full drug information
Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone, Baldex)

Postulated mechanisms of action in brain tumors include reduction in vascular
permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased
CSF production.
Antineoplastic Agent, Alkylating Agent
Class Summary
These agents inhibit cell growth and proliferation.
View full drug information
Temozolomide (Temodar)

Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable;
approximately 35% crosses the blood-brain barrier.
FOLLOW UP
Further Inpatient Care
Management of low-grade astrocytomas is controversial. The tumors may be
radiographically stable and clinically quiescent for long periods after the initial
presentation.
Therapeutic options include observation, radiation, and resection with and without
radiation. Unless an astrocytoma is resected completely, radiation therapy should be
considered.
In higher-grade lesions, even if gross total resection is confirmed radiographically,
postoperative radiation is indicated because microscopic disease remains.
If no resection is undertaken and radiation is contemplated, a stereotactic biopsy is
recommended to establish the histological grade of the tumor definitively.
Further Outpatient Care
Patients should consult a neurologist to observe the progression of neurological signs
and symptoms and to manage steroid and anticonvulsant regimens.
Outpatient neurosurgery observation is necessary for tumor monitoring and
management of hydrocephalus if a shunt has been placed.
Postoperative and postirradiation chemotherapy trials using nitrosourea and other
agents are likely to benefit patients with malignant astrocytomas, but the benefit for
patients with well-differentiated astrocytomas is questionable.
Frequency of postoperative MRI is determined by both the neurosurgeon and other
physicians involved in the ongoing care of the patient, including the neurooncologist and
radiation oncologist.
Inpatient & Outpatient Medications
Corticosteroids, antiepileptic agents, and GI prophylaxis should be employed.
Transfer
If surgery is anticipated, patients should be transferred to institutions with an
appropriately equipped and adequately staffed neurosurgical intensive care unit for
postoperative monitoring.
Patients may require extensive or focused postoperative rehabilitation that may
necessitate transfer to specialized institutions dedicated to physical and occupational
therapy.
Complications
Although neurological injury (potentially devastating) and death must be mentioned,
neurosurgery for astrocytomas is generally intended to decrease tumor bulk while
avoiding permanent neurological injury. Transient deficits due to local swelling or injury
may occur, but they often improve after a course of physical therapy and rehabilitation.
Prognosis
Prognosis for survival after operative intervention and radiation therapy can be
favorable for low-grade astrocytomas.
For those patients who undergo surgical resection, the prognosis depends on whether
the neoplasm progresses to a higher-grade lesion.
For low-grade lesions, the mean survival time after surgical intervention has been
reported as 6-8 years.
In the case of anaplastic astrocytoma, symptomatic improvement or stabilization is the
rule after surgical resection and irradiation. High-quality survival is observed in 60-80%
of these patients. Factors such as youth, functional status, extent of resection, and
adequate irradiation affect the duration of postoperative survival.
Recent reports indicated that irradiation of incompletely resected tumors increased 5-
year postoperative survival rates from 0-25% for low-grade astrocytomas and from 2-
16% for anaplastic astrocytomas. Furthermore, the median survival rate of patients with
anaplastic astrocytoma who undergo both resection and irradiation has been reported to
be twice that of patients receiving only operative therapy (5 y vs 2.2 y).

Overview
Presentation
Workup
Treatment
Medication
Follow-up

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