Brain Tumors: Primary
WHAT ARE BRAIN TUMORS?
Brain tumors are composed of cells that exhibit
unrestrained growth in the brain.
They can be benign (noncancerous, meaning that
they do not spread elsewhere or invade surrounding
tissue) or malignant (cancerous).
Malignant brain tumors are further classified as
either primary or secondary tumors.
Primary tumors start in the brain, whereas secondary
tumors spread to the brain from another site such as the
breast or lung. (In this report, the term "brain
tumor" will refer mainly to primary malignant
tumors, unless otherwise specified.)
Benign tumors represent half of all primary brain
tumors. Their cells look relatively normal, grow slowly,
and do not spread (metastasize) to other sites in the
body. Benign tumors can still be serious and even
life-threatening if they are situated in vital areas in
the brain where they exert pressure on sensitive nerve
tissue or if they increase pressure within the brain.
While some benign brain tumors may pose a health risk,
including risk of disability and death, most are usually
successfully treated with techniques such as surgery.
Secondary (Metastatic) Malignant Brain Tumors
A secondary (metastatic) brain tumor occurs when
cancer cells spread to the brain from a primary cancer
in another part of the body. Secondary tumors are about
three times more common than primary tumors of the
brain. Usually, multiple tumors develop. Solitary
metastasized brain cancers may occur but are less
common. Most often, cancers that spread to the brain to
cause secondary brain tumors originate in the lung,
breast, kidney, or from melanomas in the skin.
Primary Malignant Brain Tumors
A primary malignant brain tumor is one that
originates in the brain itself. Although primary brain
tumors often shed cancerous cells to other sites in the
central nervous system (the brain or spine), they rarely
spread to other parts of the body.
Brain tumors are generally named and classified
according to the following:
- the normal brain cells from which they originate,
- the location in which the cancer develops.
The biologic diversity of these tumors, however,
makes classification difficult, and some experts believe
that more specific categories are needed. [For a
description of these tumors, see tables of
individual brain tumors .]
Categories of Primary Glioma Brain Tumors by Cell
About half of all primary brain tumors are known
collectively as gliomas. They are cancerous forms
of glial cells, which are the building-block
cells of the connective, or supportive, tissue in the
central nervous system. There are several glial cells
types from which gliomas form and are named:
- Astrocytomas are primary brain tumors
derived from astrocytes, which are
star-shaped glial cells. Normal astrocytes provide
nutrients, support, and insulation for nerve cells
and are one of the primary neurologic cells in the
body. The malignant astrocytomas called
glioblastomas account for 23% of brain tumors and
are the most common ones.
- Oligodendrogliomas develop from oligodendrocyte
glial cells, which form the protective coatings
around nerve cells. Although oligodendrogliomas were
thought to represent about 5% of all gliomas, more
recent evidence suggests they may comprise about 20%
of gliomas. Pure oligodendrogliomas, however, are
rare and in most cases they occur in mixed gliomas.
( See below).
- Ependymomas are derived from ependymal
cells, which line the ventricles
(fluid-filled cavities) in the lower part of the
brain and the central canal of the spinal cord. They
constitute about 6% of all primary tumors in the
central nervous system. About 30% of these tumors
occur in the spinal cord.
- Mixed Gliomas contain a mixture of
malignant gliomas. About half of these tumors
contain cancerous oligodendrocytes and astrocytes.
It should be noted that gliomas may also contain
cancer cells derived from brain cells other than glial
cells. [For a description of these tumors, see
tables of individual brain tumors .]
Categories of Brain Tumors by Location
Some brain tumors are categorized by their location
in the brain. Such tumors often contain gliomas but are
also frequently a mixture of different cell types. [For
a description of these tumors, see tables of
individual brain tumors .]
Meningiomas. Meningiomas are usually benign
tumors that develop in the membranes that cover the
brain and spinal cord (the meninges).
They are not technically classified as brain tumors but
they have similar symptoms and develop within the brain,
and so in practical terms, they are considered to be
brain tumors. In fact, they comprise 20% of all primary
brain tumors. They occur more often in women than in
men. Most grow very slowly, and the majority of people
who have them never know they are present. Malignant
forms called anaplastic meningiomas and hemangiopericytomas
are less common and are difficult to remove surgically.
Cerebral Astrocytomas. Gliomas that develop
inside the brain often occur in the cerebral
hemispheres (the right and left sides of the brain).
In such cases, they are referred to as cerebral
astrocytomas. Gliomas sometimes occur in another part of
the brain called the cerebellum, which is responsible
for balance and coordination. In such cases, the term cerebellar
astrocytoma is used.
Brain Stem Gliomas. Brain stem gliomas develop in
the lowest portion of the brain. The brain stem connects
the cerebrum (the higher centers of the brain) to
the spinal cord. The brain stem is thought to be
the primitive brain because it controls the most basic
functions. It consists of three primary parts:
- The medulla, which regulates breathing,
swallowing, blood pressure, and heart rate.
- The pons (meaning
₯?bridge₪?#157;) that links the
cerebellum to the cerebrum.
- The midbrain, which helps control vision
always located in the cerebellum, which is at the
base and toward the back of the brain. They represent
about 3% of all brain tumors.
Pituitary Tumors. Pituitary tumors comprise about
10% of primary brain tumors and are often benign,
slow-growing masses in the pituitary gland.
Other Brain Tumor Locations.Optic nerve gliomas
occur in the optic nerve, which is located behind the
eye. Acoustic neuromas make up 7.5% of brain tumors.
WHAT ARE THE SYMPTOMS OF BRAIN TUMORS?
Brain tumors produce a variety of symptoms ranging
from headache to stroke. They are great mimics of other
neurologic disorders. Symptoms occur if the tumor
directly damages the nerves in the brain or central
nervous system or if its growth imposes pressure on the
brain. Some gliomas develop gradually and symptoms may
be subtle for a long time, making an early diagnosis
Headache is probably the most common symptom of a
brain tumor. It should be strongly emphasized, however,
that everyone has headache, and they rarely represent an
underlying brain tumor. Headaches caused by brain tumors
may vary depending on the location, and can include some
of the following features:
- Steady and worse upon waking in the morning and
clears up within a few hours.
- Persistent non-migraine headache that occurs while
sleeping and is also accompanied by at least one
other symptom (e.g., vomiting, confusion).
- May or may not be throbbing, depending on location
of the tumor.
- Accompanied by double vision, weakness, or
- May worsen with coughing or exercise or with a
change in body position.
- Sometimes accompanied by neck pain.
Gastrointestinal symptoms, including nausea, are also
common. Nausea and vomiting, in fact, often occur in
children with brain tumors and in all people with brain
stem cell tumors.
Seizures occur in between 15% and 95% of patients,
depending on the location of the tumor.
- Tumors are more likely to be localized and affect
one area of the brain. In such cases they can cause partial
seizures. In this case, a person does not lose
consciousness but may experience confusion, jerking
movements, tingling, or odd mental and emotional
- Generalized seizures, which can cause loss of
consciousness, are less common, since they are
caused by disturbances of nerve cells in diffuse
areas of the brain.
Sometimes the only symptoms are mental changes, which
may include the following:
- memory loss,
- impaired concentration,
- problems with speech and reasoning, and
- increased sleep.
Other Significant Symptoms
Other important symptoms include the following:
- Gradual loss of movement or sensation in an arm or
- Unexpected visual disturbance (especially if it is
associated with headache), including vision loss
(usually of peripheral vision) in one or both eyes
or double vision.
- Hearing loss with or without dizziness.
- Speech difficulty.
Symptoms Associated with Specific Tumors
Specific symptom syndromes may help identify the
tumor. The following are some examples.
Symptoms of Brain Stem Gliomas. Sudden onset
of symptoms that include vomiting (usually just after
waking), a clumsy walk, muscle weakness on one side of
the face, difficulty in swallowing, slurred or nasal
speech, as well as impaired hearing or vision.
Symptoms of Glioblastoma Multiforme. Rapid
onset and worsening of symptoms that include headaches,
seizures, memory loss, and changes in behavior.
Symptoms of brain tumors that indicate an emergency
condition requiring prompt intervention include the
- Pupil dilation.
- A fixed gaze.
- Paralysis on one or both sides of the body.
- Blindness or defective vision in one eye.
WHO GETS BRAIN TUMORS?
General Risk Factors
An estimated 39,550 benign or malignant primary brain
tumors are currently expected to be diagnosed in America
this year. About 21,670 of these tumors will be
malignant. Nearly 360,000 people in the US are currently
living with brain cancer.Men are at higher risk for most
brain tumors than women. Primary malignant brain tumors
are still uncommon and represent only 1.3% of all
cancers diagnosed in the United States and 2.4% of all
deaths due to cancer.
Primary brain cancers are rare, occurring in slightly
more than 11 people per 100,000 per year. There has been
some evidence of a growing incidence of brain cancer
among the elderly since the 1980s. The increase,
however, is most likely due to the rise in incidence of
non-Hodgkin's lymphomas--which can occur in the brain.
When this malignancy is eliminated, any increase in
other tumors is not significant.
The average age of diagnosis for brain tumors is 57,
and about 90% of primary brain tumors occur in adults,
they can develop at all ages, usually peaking in two age
- In adults between the ages of 55 and 65.
- In children between the ages of 3 and 12.
Risk Factors in Children. Tumors in the
central nervous system are now the most common primary
cancers in children, but they are still rare. An
estimated 3,110 benign or malignant brain tumors are
expected to be diagnosed in children each year. Brain
tumors in children are more likely to occur in the
cerebellum, the midbrain, or the optic nerve.
The incidence has increased over the past years, but
there is some evidence that this increase is only due to
better diagnostic procedures. The mortality rate has
actually decreased. Researchers have attempted to
uncover risk factors for childhood brain cancer. Some
association between a higher risk and the following
conditions have been observed:
- Children treated with radiation to the head for
leukemia and who have a specific genetic defect may
face a high risk for brain cancer. (It should be
noted that for children without this defect, the
risk is very small.)
- Having parents with specific cancers. (According
to a 2000 study, having parents with nervous system
cancers, colon cancer, or cancer in the salivary
glands increased the risk of specific brain tumors
in their children.)
The risk for primary brain tumors in Caucasians is
higher--as much as twofold depending on type--than in
Environmental or Occupational Risk Factors
Radiation. The only proven risk factor for
brain tumors to date is high-energy radiation from ions
(such as with radiation treatment).
Studies on the effects of lower-energy radiation,
such as microwaves and electromagnetic fields, have been
uncertain. One study reported that men whose jobs
exposed them to electromagnetic fields had higher rates
for brain cancer, although a more recent study found a
higher risk only in men who were also exposed to
chemicals (petroleum, solvents, lead, pesticides and
A 2002 study on Korean War veterans highly exposed to
microwaves from radar equipment reported no excess risk
for brain cancer--or any other malignancy--over a
40-year period. Studies in both 2000 and 2001 found no
evidence to suggest a higher risk with cellular phones
and other wireless devices that use radiofrequency.
Chemical and Metals in Brain Tumors. High
exposure to a number of metals and chemicals have been
associated with brain tumors, such as the following:
- High exposure to certain chemicals, including
vinyl chloride and petroleum products, has been
associated with brain tumors.
- High levels of lead, arsenic, or mercury exposure
have been linked to a higher risk. One study
suggested that lead exposure was particularly
associated with meningiomas. It is unknown whether
these associations are real, and confirmatory
studies are needed.
- There has been some suggestion of a higher risk
with exposure to pesticides.A major study of
pesticides is underway, but results are not in yet.
A 2003 study indicated that parental exposure to
pesticides or herbicides did not appear to be
important in increasing risk for brain cancer in
Brain cancer is uncommon, and, over the course of
their lifetime, many people are exposed to these
chemicals, many of which are very common. To date, there
has been no clear evidence that implicates any specific
industrial chemical or metal.
About 5% of primary brain tumors are associated with
hereditary disorders. They include the following:
- Li-Fraumeni cancer family syndrome.
- Tuberous sclerosis.
- Von Recklinghausen℮?s disease (neurofibromatosis).
- Von Hippel Lindau disease.
- Familial polyposis (Turcot's syndrome).
- Osler-Weber-Rendu syndrome.
A 2002 study reported a higher risk for brain cancers
in patients who had undergone organ transplantations.
Researchers believed that the drugs used to suppress the
immune response after the procedures may increase the
Medical Conditions Associated with a Lower Risk for
A 2002 study reported lower risks for brain cancers
in individuals with allergies and autoimmune diseases
(e.g., diabetes type 1). Autoimmune diseases were also
associated with a lower risk for meningiomas. The cause
of this possible association remains unknown.
Studies have also found an association between lower
risk for gliomas and a history of infection with
varicella zoster, the virus that causes chicken pox and
A number of defective genes are involved in the
cancer process. Genes that cause cancer proliferation
(called oncogenes) and those that normally suppress
tumors but are defective (tumor suppressor genes) may
play separate roles in a step-by-step process leading to
primary brain cancer. Several avenues of investigation
are in progress to determine both basic causes and the
triggers for such genetic defects.
Specific Genetic Abnormalities. A number of
specific brain tumors, including glioblastomas,
anaplastic astrocytomas, and medulloblastomas,
are the result of abnormal or missing genes:
- For example, researchers have discovered a
defective gene MMAC1 (Mutated Multiple Advanced
Cancers) in the majority of the glioblastomas
(although not low-grade gliomas). The MMAC1 gene
determines how aggressive a tumor will be.
- Another defective gene, known as the Patched 2
gene, which appears to promote tumor growth, has
been found in about half of all medulloblastomas.
[For description of these tumors, see tables
of individual brain tumors .]
Inherited Genetic Factors. A large population
study reported that family clusters of brain cancer
occurred in a small fraction of astrocytomas, indicating
that inherited factors may play a direct role in some
Acquired Genetic Defects. Genetic
abnormalities that cause brain tumors are not usually
inherited but mostly occur as a result of environmental
insults or other factors that affect genetic materials
(DNA) in the cells. Researchers are studying a number of
environmental assaults that might trigger brain tumors
in susceptible individuals. Among them are the
- Abnormal development in the womb.
- Ionizing radiation.
- Electromagnetic fields.
Currently estimated 13,100 people die from malignant
brain tumors a year.Recent advances in surgical and
radiation treatments have significantly extended average
survival times and can reduce the size and progression
of malignant gliomas. In general, survival rates are
highest in younger people and lowest in the elderly.
Five Year Survival Rates by Age Group
0 to 19 years
20 to 44 years
45 to 64 years
Data From: 2002-2003 Primary Brain Tumors in
the United States Statistical Report. Fact Sheet
(1973-1999 data). Brain Tumor Registry of the
United States http://www.cbtrus.org/factsheet.htm
In general, studies are reporting that patients who
survive the first two years after a diagnosis of a brain
tumor have at least a 70% chance of surviving for at
least five years. The best progress over the recent
decades has been made specifically in the following:
in both children and adults. Long-term survival
rates are now about 60% in children after treatment
the most common malignant brain tumor in this age
group. (New treatments, however, may significantly
improve these rates.)
- Nonmalignant astrocytomas and oligodendrogliomas
Unfortunately, the majority of primary brain tumors,
notably anaplastic astrocytomas and glioblastoma
multiforme, are only rarely curable.
Specific Effects of Tumors on Function
The specific effects of tumors on the brain can
causes seizures, mental changes, and mood, personality,
and emotional changes. Such effects can be devastating
to the patient and the caregivers. A number of
treatments are available that help alleviate these
complications, and patients and family members should
discuss these with their physician. [ See also
What Are Some Treatments for Complications of Brain
HOW ARE BRAIN TUMORS DIAGNOSED?
A neurological exam is usually the first test given
when a patient complains of symptoms that suggest a
brain tumor. The exam includes checking eye movements,
hearing, sensation, muscle movement, sense of smell, and
balance and coordination. The physician will also test
mental state and memory.
X-rays of the skull were once standard diagnostic
tools but are now performed only when more advanced
procedures are not available. Advanced imaging
techniques have dramatically improved the diagnosis of
brain tumors in recent years.
Magnetic Resonance Imaging. Magnetic resonance
imaging (MRI) is the gold standard for diagnosing a
brain tumor. It does not use radiation and provides
pictures from various angles that can enable doctors to
construct a three-dimensional image of the tumor. It
gives a clear picture of tumors near bones, smaller
tumors, brainstem tumors, and low-grade tumors. MRI is
also useful during surgery to show tumor bulk, for
accurately mapping the brain and for detecting response
A variant called magnetic resonance spectroscopy (MRS)
is capable of providing information on the activity of
the brain using magnetic resonance imaging. MRS is
proving to be accurate for distinguishing dead
(necrotic) tissue caused by previous radiation
treatments from recurring tumor cells in the brain, a
difficult diagnostic issue.
Computed Tomography. Computed tomography (CT)
uses a sophisticated x-ray machine and a computer to
create a detailed picture of the body's tissues and
structures. It is not as accurate as an MRI and does not
detect about half of low-grade gliomas. It is useful in
certain situations, however. Often, doctors will inject
the patient with an iodine dye, called contrast
material, to make it easier to see abnormal tissues. A
CT scan helps locate the tumor and can sometimes help
determine its type. It can also help detect swelling,
bleeding, and associated conditions. In addition,
computed tomography is used to check the effectiveness
of treatments and watch for tumor recurrence.
Positron Emission Tomography. Positron
emission tomography (PET) provides a picture of the
brain℮?s activity rather than its structure by
tracking substances that have been labeled with a
radioactive tracer. As with magnetic resonance
spectroscopy (MRS), it is also able to distinguish
between recurrent tumor cells from dead cells or scar
tissue, although MRS is more widely available. PET is
not routinely used for diagnosis, but it may supplement
MRIs to help determine tumor grade after a diagnosis.
Data from PET may also help improve the accuracy of
newer radiosurgery techniques.
Other Imaging Techniques. A number of other
advanced imaging techniques may be used for specific
purposes, if available or under investigation.
- Single photon emission tomography (SPECT) is
similar to PET but is not as effective in
distinguishing tumor cells from destroyed tissue
- Magnetoencephalography (MEG) scans measure the
magnetic fields created by nerve cells as they
produce electrical currents.
- Cerebral angiography involves x-rays of blood
vessels in the brain. A long, thin tube (catheter)
is threaded through blood vessels from a distant
site to the brain, and a radiopaque substance (a
substance that is impenetrable to x-rays) is
injected through it. The role of angiography in
glioma is usually limited to planning surgical
removal of a tumor suspected of having a large blood
- Radionuclide brain scintigraphy uses a radioactive
substance that is administered and absorbed by
capillaries in the tumor, which are then viewed
using imaging techniques.
- Digital holography, a new technique that provides
full three-dimensional mapping, is under
Lumbar Puncture (Spinal Tap)
A lumbar puncture is used to obtain a sample of
spinal fluid, which is examined for the presence of
tumor cells. A CT scan or MRI should generally be
performed before a lumbar procedure to be sure that the
procedure will be safe.
A biopsy is a surgical procedure in which a small
sample of tissue is taken from the suspected tumor and
examined under a microscope for malignancy. The results
of the biopsy also provide information on the cancer
In some cases, such as brain stem gliomas, a biopsy
might be too hazardous because removing any healthy
tissue from this area can effect vital functions. In
such cases, diagnosis must rely on less invasive and
possibly less accurate measures. Of promise is the
stereotactic technique (also called stereotaxy),
which uses computers to provide three-dimensional views
of very small areas. This may allow precise biopsies of
cancer cells without affecting healthy brain tissue.
Expertise in this technique is extremely important,
however, and the technique is not widely available. [For
a description of the stereotactic technique, see
Surgery under What are the Treatments for Brain
Tumors? , below.]
Determining a Prognosis
The survival rates in people with brain tumors depend
on many different variables:
- Whether the tumor is malignant or benign.
- Cancer cell type and location. (Location affects
whether the tumor can be removed surgically or not.)
[For description of specific tumors by cell type and
location, see tables of individual brain
- Tumor grade. (This is the tendency to spread and
the growth rate.) [ See Grading Tumors below.]
- Patient's age. (The outlook is poorer in the very
youngest and very oldest patients, although younger
patients who survive two years after diagnosis have
a much better outlook than older patients.)
- Patient's ability to function.
- Duration of symptoms.
Grading Tumors. Malignant primary brain tumors
are classified according to tumor grade. Grade I is the
least malignant and Grades IV and V are the most
dangerous. Grading a tumor attempts to predict its
tendency to spread and its growth rate. It is based on
the appearance of the tumor cells as seen under a
- Lower-grade (I and II) tumor cells are well
defined and almost normal-shaped. (Some primary
low-grade brain tumors are curable by surgery alone,
and some are curable by surgery and radiotherapy.
Low-grade tumors tend to have the most favorably
survival rates and high-grade the least. However,
this is not always the case. For example, some
low-grade II gliomas are at very high risk for
- Higher-grade (III and IV) tumor cells are
abnormally shaped and are more diffuse, which
indicates more aggressive behavior. (High-grade
brain tumors usually require surgery, radiotherapy,
chemotherapy, and possibly investigational
- In tumors that contain a mixture of
different-grade cells, the tumor is graded using the
highest-grade cells in the mixture, even when there
are very few of them. [ See also tables of
individual brain tumors .]
Biologic Markers. Elevated levels of certain
cancer-associated molecules or compounds may be
correlated with prognosis. For example, evidence of
genetically mutated p53 indicates a poorer prognosis in
younger patients with glioblastoma multiforme.
Elevations of epidermal growth factors (EGF) or
vascular endothelial growth factors (VEGF) suggest
aggressive tumors. High levels of the receptor for EGF (EGFR),
in fact, are found in 70% of glioblastoma specimens.
Genetic Profiles of Cancer Cells.Analyses that
identify genetic types may soon help clinicians
determine if patients with specific brain tumor cells
might response to one treatment more than another. For
example, specific genetic profiles of oligodendrogliomas
have been associated with predictable responses to
certain agents called nitrosourea alkylating agents
TABLES: COMMON BRAIN TUMORS
Common Brain Tumors:
GENERAL DESCRIPTION OF ASTROCYTOMAS:
Derived from star-shaped glial cells called
Grade and Subtype
Description of Subtypes
Low-Grade (Usually I) Astrocytomas.
Pilocytic gliomas occur mostly in children.
Tumors are well differentiated. Cells are
relatively normal and rarely metastasize. They
grow relatively slowly.
Pilocytic astrocytomas have the highest
5-year survival rates (greater than 70%).
However, even well differentiated astrocytomas
are life threatening if they are inaccessible.
Cancer may sometimes be completely removed
through surgery, particularly if it occurs in
For recurrence or residual tumors,
reoperation, radiotherapy, or chemotherapy may
be given, depending on the circumstances. Repeat
surgery for cerebellar astrocytoma is often very
successful. For those who fail radiotherapy and
chemotherapy, investigative drugs are used.
Low-Grade (II) Astrocytomas.
Fibrillary, protoplasmic, and protoplasmic
astrocytomas. Some pleomorphic
Tumors are well differentiated. Cells are
relatively normal and less malignant than those
in higher grades. They grow relatively slowly
but can spread. Survival rates average five
years but people can survive for a decade or
Pleomorphic xanthoastrocytomas have a
relatively favorable prognosis, but can recur
and demonstrate aggressive clinical behavior.
Low-grade astrocytomas generally occur in
young adulthood, with a peak incidence in 30s
Surgery, if possible, plus radiotherapy.
Surgery alone in certain children, if possible.
Trials on postoperative radiotherapy include the
following: Radiotherapy with or without
chemotherapy; Low-versus-high radiotherapy doses
(studies suggest results are the same and
high-dose causes more side effects); Deferring
radiotherapy until tumor progresses and symptoms
occur. (A major 2002 study confirmed earlier
ones that suggest that this approach has the
same 5-year survival benefits--about 65%--as
immediate postoperative radiotherapy.)
Malignant (High-grade III and IV)
Astrocytomas. Anaplastic astrocytoma (gemistocytic
and some pleomorphic xanthoastrocytomas).
Usually mid-grade (III).
Tumors grow more rapidly than lower grades
and infiltrate other nearby healthy cells. Not
well-differentiated. Five-year survival rates
are about 30%. Recurrence is common.
Treatment same for all high-grade malignant
Surgery, with removal of as much of tumor as
possible followed by radiotherapy, with or
The addition of chemotherapy, particularly
being able to take more than 6 cycles, appears
to improve survival rates. Carmustine (BCNU)
most effective agent at this time. Other agents
and treatment sequences are under investigation.
For example, temozolomide is showing promise for
many patients, including the elderly. Topotecan
may also be useful with other agents or with
For recurring gliomas, surgery with placement
of wafers that release carmustine (Gladiel
wafers) is the only proven beneficial therapy to
date. Combinations, such as procarbazine and
carmustine, provide benefits for recurrent
anaplastic astrocytomas. Single agents may be
less toxic and as helpful for other recurrent
gliomas. Temozolomide has been approved in
Europe for high-grade recurrent gliomas and is
proving to be beneficial. Other trials include
the following: drugs that block small molecules
involved in tumor growth; radioimmunotherapy
using monoclonal antibodies; advanced
radiotherapy techniques; intraarterial
High-grade (IV and V).
Glioblastoma (notably glioblastoma multiforme
Very rapidly growing tumors; spread quickly.
Represents about 25% of all primary brain
tumors. Most common in older adults (over 55)
and affect more men than women. Recurrences are
common in patients who achieve long-term
Common Brain Tumors:
GENERAL DESCRIPTION OF EPENDYMOMAS:
Derived from cells that line the ventricles
(fluid-filled brain cavities) and spinal cord
central canal. Do not usually spread into
normal brain tissue. Can block exits for
cerebrospinal fluid and cause hydrocephalus.
They constitute about 4% of all central nervous
system tumors in adults and 10% of these tumors
in children. About 30% of ependymomas develop in
the spinal column.
Grade and Subtype
Descriptions of Subtypes
Myxopapillary ependymoma (found in the
Subependymoma (found in one of the
No or very slow growth. In addition to grade,
risk is also based on location of the tumor.
Tumors on the spinal cord are more accessible
than those in the fourth ventricle or in the
middle of the lower back portion of the brain.
Can often be removed and cured with surgery,
particularly those on spinal cord. Radiation may
be needed. Chemotherapy (avoid radiation, if
possible) in children under six.)
Papillary, cellular, and clear cell
Slow growth. Usually affect adults.
Surgery alone or followed by radiotherapy.
For those who fail radiotherapy, possible use of
nitrosourea-based chemotherapies or
Spread to the spinal fluid.
Surgery followed by radiotherapy to brain and
spinal cord. Possible shunt.
Primitive neuroecto-dermal tumor (PNET).
Composed of malignant forms of early,
undeveloped nerve cells called neuroblasts.
(This malignancy is also referred to as
Very rare, but more common in children.
Primitive nerve cells that grow very rapidly.
Usually occur in cerebellum.
Surgery followed by radiotherapy to brain and
spinal cord. Chemotherapy in young children.
Investigative high-dose chemotherapy with stem
cell rescue for children with relapsed cancer.
Common Brain Tumors:
DESCRIPTION OF OLIGODENDROGLIOMAS:
They develop from oligodendrocyte glial
cells. These cells form the protective coatings
around nerve cells. Pure cell types are rare.
Most often occur in mixed gliomas. Categorized
as either low- or high-grade. Most are low grade
Description of Grade
Low Grade: Low grade difficult to tell
from astrocytomas, although they are usually
calcified. Very likely to bleed. Usually spread
along nerve pathways of the brain and spine and
rarely outside this area. In spite of difficulty
in removing surgically, in some patients
survival can be 30 to 40 years. Usually have
better prognosis than astrocytomas of equal
grade. Occur mostly in middle-aged adults,
although there is also a small peak of incidence
Treatment usually delayed until progression
Surgery to remove whole tumor. Radiotherapy
often follows in all adults over 40 or in anyone
in which tumor cannot be completely removed.
Solid evidence is lacking on this approach,
however, and there is some debate on its
Trials using chemotherapy after radiation are
promising. Two-thirds of patients respond to PCV
(combination of procarbazine, lomustine and
vincristine.) Sustained remissions averaging 16
years often achieved. Pure oligodendrogliomas
respond better than mixed gliomas. Temozolomide
is showing promise as second-line treatment.
Others under investigation.
Trials of additional chemotherapy for less
well-differentiated tumors or for residual
tumors after surgery.
Immediate treatment. Surgery to remove the
whole tumor, if possible. Radiation typically
follows surgery. Chemotherapy treatments either
before or with radiation. Standard agents are
limited. Experts recommend trying investigative
agents. Temozolomide and retinoic acid may be
useful. Possible additional agents include
melphalan, thiotepa, carboplatin, cisplatin, and
(A number of biologic markers may help
identify specific oligodendrogliomas that will
respond better or worse to specific treatments.)
Common Brain Tumors: Mixed
GENERAL DESCRIPTION OF MIXED GLIOMAS:
Mixed Glioma s contain a mixture of
malignant gliomas. About half of these tumors
contain cancerous oligodendrocytes and
Grade determined by the highest-grade cell
present in the tumor.
Same as for oligodendroglioma.
Some Common Brain Tumors by
They are found in the membranes around the
brain and spinal column. They are usually benign
and rarely invasive. In such cases, long-term
outlook is very favorable. (Malignant forms,
anaplastic meningiomas and hemangioperictyomas
are uncommon and occur in about 2% of cases.)
Usually watchful waiting. Aggressive surgery
the treatment of choice, if possible, although
20% recur after 10 years. Malignant forms and
those at the base of the skull difficult to
impossible to remove surgically. Stereotactic
radiosurgery or fractionated external beam
radiotherapy showing promising results for some
Cerebellar astrocytomas (located in
Located in the cerebellum. Usually low-grade,
but depends on cell type. If surgical removal is
complete, up to 90% survival rates. More common
in children than adults.
Surgery primary treatment. Radiotherapy if
removal is incomplete.
Brain Stem Gliomas
About 60% to 70% of brain stem tumors are
diffuse, which are likely to spread and have a
rapid onset of symptoms. Focal tumors tend to be
solid or cyst-like; they generally develop
gradually. Occurs in both children and young
Radiation is usual treatment. Tumors in this
area are rarely removed surgically since the
nerve tissue in this area is responsible for
vital life functions. Slow-growing tumors may
only require watchful waiting. Trials using
advanced radiotherapy techniques, gene therapy,
immunotherapy, and other experimental drugs.
Occurs in cerebellum (the lower portion of
the brain), brainstem, and spinal cord. Usually
fast-growing aggressive cells. They are the most
common brain tumors in children and young
people. Cause between 15% and 20% of brain
tumors in this patient population. With
aggressive therapy, in children 5-year survival
rates between 60% and 80% have been reported. In
patients who survive for two years after
diagnosis, long-term survival rate is nearly
Treatment is usually surgery and reduced-dose
radiotherapy with or without chemotherapy.
Research in 2002 detected a signal pathway
required for tumor growth. Blocking this pathway
with specific agents, such as cyclopamine, may
have a role in this cancer. In children,
treatment may be reduced-dose radiotherapy
followed by platinum-based chemotherapy.
Optic Tract Gliomas
Spread along the optic nerve. Usually slow
growing. Most often in children under 10.
Children with these tumors often have vision and
Usually surgery if one eye is involved.
Possible chemotherapy or radiation.
The approach for treating brain tumors is to reduce
the tumor as much as possible using surgery, radiation
treatment (also called radiotherapy), chemotherapy, or
investigative procedures. Such treatments are used alone
or, more commonly, in combinations. With some very
slow-growing cancers, such as those that occur in the
midbrain or optic nerve pathway, patients may be closely
observed and not treated until the tumor shows signs of
growth. The intensity, combination, and sequence of
these treatments depends on the glioma subtype, its size
and location, and patient age, health status, and
Recent advances in surgical and radiation treatments
have significantly extended average survival times
compared to those of standard therapy. Investigative
treatments, such as monoclonal antibodies, are also
showing promise. Patients or their caretakers should
discuss all options thoroughly with a specialist in
brain cancer. Different specialists may be needed to
help manage symptoms.
Because of the low-cure rates of most malignant brain
tumors, support for the patients and their families is a
critical component of treatment and management. In
response to one survey of patients with gliomas, experts
made a number of recommendations to help both patients
- Any physical impairment that could benefit from
home equipment or physical therapy should be
identified and treated.
- Patients should discuss emotional as well as
physical issues with their physicians. Depression,
for instance, can be medically treated.
- Relaxation techniques, meditation, and spiritual
resources can be extremely helpful. Support groups
are beneficial, but experts recommend separate
groups for patients and their families.
A 1999 study gave some comfort by reporting that
children with cancer have no more emotional or social
problems than their healthy peers. In fact, teachers and
students reported that, on average, such children tended
to be less aggressive and more likable than their peers.
It is more likely that the parents and caregivers suffer
more emotionally. Caregivers themselves must seek help
for the inevitable stress, depression, and tension
arising from their difficult role.
Although there is little evidence that dietary
measures have any effect on brain cancer, some studies
suggest the following might be helpful.
Dietary Restriction. Calorie restriction has
been associated with cancer protection in some animal
studies. One study reported brain tumor regression in
mice that were put on a restrictive diet (calories are
reduced but without causing nutritional deficiencies).
Limiting calories appeared to help slow down tumor
angiogenesis (blood vessel growth, which feeds the
tumor). Not all animal studies support these results,
however, and there are no human studies on this
Soy.One study suggested that compounds in soy,
such as genistein, suppresses invasiveness and growth of
some cancers, including gliomas. It is not known whether
this approach is beneficial to patients with brain
WHAT ARE THE SURGICAL TREATMENTS FOR BRAIN TUMORS?
Surgery is usually the first step in treating most
brain tumors, although in some cases, such as most brain
stem gliomas, it may be too dangerous. The object of
most brain tumor surgeries is to remove or reduce as
much of its bulk as possible. By reducing the size,
other therapies, particularly radiotherapy, can be more
effective. (Although there have been significant
advances in brain surgeries, some experts argue that in
high-grade gliomas extensive surgery may not improve
survival rates at all and patients are best served by
The standard procedure is called craniotomy:
- The neurosurgeon removes a piece of skull bone to
expose the area of brain over the tumor.
- The tumor is located and then removed.
- The surgeon has various surgical options for
breaking down and removing the tumor.
- Standard surgical procedures.
- Laser microsurgery (which produces great heat and
vaporizes tumor cells).
- Ultrasonic aspiration (which uses ultrasound to
break the glioma tumor into small pieces, which are
then suctioned out).
Relatively benign, grade I gliomas may be treated
only by surgery. Some controversy exists over whether
surgery for low-grade astrocytomas improves survival,
although insufficient research has been conducted to
prove its benefits for these gliomas. Most malignant
tumors require additional treatments, including repeat
The surgeon℮?s skill in removing the tumor as
completely as possible is critical to survival. No one
should be shy about requesting the number of similar
procedures a surgeon has performed. (Asking for
complication rates may not be useful, since a very
experienced surgeon might operate on many high-risk
Additional Procedures to Enhance Brain Surgery
In most cancers outside the brain, surgical removal
of a tumor usually involves taking out surrounding
healthy tissue to be sure all cancer cells are gone. In
the brain, however, removing healthy nearby nerve tissue
can be as disastrous for the patient as the cancer
itself. Special techniques have been developed to allow
maximum removal of tumor while protecting healthy brain
Stereotaxy. Stereotaxy has become a
useful adjunct to both surgery (stereotactic surgery)
and radiotherapy (stereotactic radiotherapy). [ See
Stereotactic Radiosurgery under How Is
Radiotherapy Used in the Treatment of Brain Tumors?]
Cortical Localization. Cortical localization,
or stimulation, uses a probe that passes a tiny
electrical current to delicately stimulate a specific
area of the brain. This produces a visible response of
the body part (such as a twitch in a leg), which the
stimulated region of the brain controls. The surgeon
then knows to avoid those areas during the operation.
Image-Guided Surgery. Image guided surgery
uses a three-dimensional picture of the patient℮?s
brain derived from computed tomography (CT) or magnetic
resonance imaging (MRI) scans. An advanced technique
called high-field interventional MR imaging (iMRI) is
particularly accurate in identifying the tumor, but it
is not widely available. The image, with various views
of the brain, is displayed on a monitor in the operating
room. During surgery, as the surgeon's instrument
touches a part of the brain, a camera sends the image to
a computer, which calculates the position of the
surgical tool and displays it in its proper location on
the 3-D image. The surgeon then can look at the monitor
and see what structures to avoid.
Magnetic-Tipped Catheters.Neurosurgeons are
investigating the use of a technique in which external
magnetic fields direct a magnet-tipped flexible catheter
to the tumor site through a path that avoids areas of
the brain that could cause harm.
HOW IS RADIOTHERAPY USED FOR TREATING BRAIN TUMORS?
Role of Radiotherapy in Brain Tumors
Radiotherapy plays a central role in the treatment of
most brain tumors, whether benign or malignant.
Radiotherapy after Surgery. Even when it
appears that the entire tumor has been surgically
removed, microscopic cancer cells often remain in the
surrounding brain tissue. Radiation targets the residual
tumor with the goal of reducing its size or stopping its
progression. If the entire tumor cannot be removed
safely, postoperative radiotherapy is often recommended.
Even some benign gliomas may require radiation, since
they may be life-threatening if their growth is not
Radiotherapy When Surgery Is not Appropriate.
Radiotherapy may be used instead of surgery for
inaccessible tumors or for tumors that have properties
that are particularly responsive to radiotherapy.
Radiotherapy and Chemotherapy (Radiochemotherapy).
Combining chemotherapy with radiotherapy is beneficial
in some patients with high-grade tumors.
Specific Radiation Treatments
Various radiation treatments are now available.
- Conventional radiotherapy uses external beams
aimed directly at the tumor and is usually
recommended for large or infiltrating tumors. It
begins about a week after surgery and continues five
days per week for six weeks. It should be noted that
older adults have a more limited response to
external-beam radiation therapy than younger people.
For tumors that are highly localized, the radiation
therapist has a choice of other radiation treatments:
- Brachytherapy (also called interstitial radiation)
uses radioactive ₯?seeds₪?#157;
implanted directly in the tumor site. It is used as
a booster to external beam radiation for patients
with malignant astrocytoma. Brachytherapy appears to
prolong survival in some aggressive gliomas. It may
also be a safe and effective treatment for some
- Conformal three-dimensional conformal radiation
uses high-dose radiation beams shaped to match the
shape of the glioma. This technique is highly
targeted and, in certain cases, may even be used
with some success for patients who have had previous
- Hyperfractionated radiation uses many small
radiation doses to deliver a high total dosage of
- A balloon catheter (GliaSite) that delivers
radiation to the tumor cavity after surgery is
Stereotactic radiosurgery has been developed to allow
highly targeted radiation to be delivered directly to
the small tumors while avoiding healthy brain tissue.
The term radiosurgery is used because the destruction is
so precise that it acts almost like a surgical knife.
Some studies are finding that stereotactic radiosurgery
improves survival, even in patients with the highly
aggressive glioblastoma multiforme brain cancer. The
procedure is being tested to boost standard
Benefits of Stereotaxy. There are a number of
benefits for stereotaxy:
- Stereotaxy allows precisely focused, high dose
beams to be delivered to gliomas less than 1.25 inch
- Investigators have found that stereotactic
radiosurgery can help them reach small tumors
located deep in the brain that were previously
- Sometimes with stereotaxy only a single treatment
may be needed.
- Unlike traditional radiotherapy, stereotactic
radiotherapy can be repeated, so it is useful for
recurrent tumors when a patient has already received
standard radiation treatments.
- Combining stereotaxy with techniques that gauge
speech and other mental functions in patients who
are awake during the procedure can allow removal of
brain tissue with a lower risk for complications in
areas that affect such functioning.
The Planning Procedure. Stereotactic
radiosurgery usually begins with a series of steps
designed to plan the radiation target:
- First, the patient is given a local anesthetic. In
the standard operation, the patient's head must be
totally immobilized by screwing a device known as a stereotactic
frame into the patient's skull. (The frame
procedure is effective only on brain tumors that
have regular margins.) The frame is removed as soon
as the whole procedure has been completed (about
three to four hours.)
- A three-dimensional map, usually using magnetic
resonance imaging scans (MRI), is made of the
- A computer program calculates dosage levels and
specific areas for radiation targeting.
Advanced imaging techniques are now allowing frameless
stereotaxy, which eliminates the frame and may be
effective on more tumors. For example, high-field
interventional MR imaging (iMRI) uses a guidance system
based on cruise-missile technology to calculate the
slightest variations in movements of the head and the
location of the tumor relative to these movements. These
calculations are then used to target the radiation beams
directly on the tumor, even if the patient℮?s head
is moving slightly.
Delivery of Radiation Beams. Once the
preliminary planning stage has been completed, treatment
begins. A number of advanced machines, such as the gamma
knife, adapted linear accelerator (LINAC),
and cyclotron, are being used with stereotaxy and
can deliver very focused beams of radiation. Actual
treatment takes 10 minutes to an hour.
- The gamma knife uses gamma rays that are sent from
multiple points to converge at a single point on the
tumor. Although each gamma-ray beam is very low
dosage, when the beams converge, the intensity and
destructive power is very high. The gamma knife is
limited to very small tumors and so is generally
useful as booster after standard radiation, surgery,
chemotherapy, or combinations.
- The linear accelerator (LINAC) produces photons
(positively-charged atomic particles) in patterns
that are matched to the tumor shape. The patient is
positioned on a bed that can be moved to allow
flexible positioning. It allows treatment over
multiple sessions of small doses (fractionated
stereotactic radiotherapy), instead of a single
session. This means that larger tumors can be
- The cyclotron is basically an atom smasher, which
produces protons that can be directed toward the
tumor. As part of this procedure, some researchers
are using boron neutron capture therapy (BNCT). BNCT
employs intravenous administration of a boron
compound, which is picked up more selectively by
tumor cells than by normal brain tissue. The
cyclotron delivers a single dose of radiation that
triggers the release of high-energy particles from
the boron that destroy nearby tumor cells. The
cyclotron is available only in a very few locations
and there have been few trials to date.
Drugs Used With Radiation
A number of drugs may be used along with radiation
that may increase the effectiveness of the treatment:
Radioprotectors. They protect healthy cells
Radiosensitizers. These agents make cancerous
cells more sensitive to radiation. For example,
combinations of the radiosensitive drugs
iododeoxyuridine, 5-FU, and hydroxyurea are promising.
Such treatments usually require aggressive use of other
protective agents to prevent severe side effects.
Radioenhancers. These drugs, such as topotecan,
increase the effects of radiation. Topotecan combined
with other drugs, such as thiotepa and carboplatin, may
help children with neuroblastoma and brain tumors. A
2002 study using topotecan for glioblastoma multiforme
was disappointing, but different methods of
administration or other similar drugs may be useful.
Efaproxiral, an investigative agent that increases
oxygen in the brain, is showing promise as a
Side Effects of Radiation
Common Side Effects. Side effects of
radiotherapy include hair loss, nausea and vomiting, and
fatigue. In some cases, radiation may worsen some
existing symptoms of brain tumors, seizures, difficulty
in swallowing, and movement problems. Fluid build-up
(edema) may occur. Such side effects are usually
temporary and treatable with steroids. Patients often
develop problems in thinking and concentration after
radiation treatments. One study suggested that
administering oxygen under pressure, called hyperbaric
oxygen, may provide some small benefits. It is sometimes
difficult to tell symptoms of the disease from those of
Tissue Injury. Radiation necrosis (total
destruction of nearby healthy tissue) occurs in about
25% of patients treated with radiation. This condition
is highly associated with reduction in mental functions.
In nearly half the cases of standard radiation therapy,
additional surgeries are needed on areas injured by
radiation. Other treatments that are showing promise for
treating necrotic tissue include administration of
oxygen and pentoxifylline (an agent that improves blood
Secondary Tumors. Of concern is a study
reporting a few cases of second tumors developing in the
areas treated with radiosurgery. The incidence appears
to be very low, but experts suggest continued
surveillance may be appropriate.
Specific Issues in Radiation Therapy for Small
Children.In small children, radiation therapy can
impair growth and learning. Precise radiation
techniques, such as three-dimensional conformal
radiation therapy, may help some children while limiting
the injury to healthy brain tissue. Growth hormone is
often used after radiotherapy and is effective in
restoring growth in many of these children. Although
there has been some concern that growth hormone may
increase the risk of relapse, a 2000 study reported
that, in fact, these children had a lower rate of
recurrence than those who did not take growth hormone.
HOW IS CHEMOTHERAPY USED IN TREATING BRAIN TUMORS?
Chemotherapy involves the use of toxic drugs to kill
cancer cells. They may be given orally, intravenously,
or administered directly into the central nervous
system. Chemotherapy is not an effective initial
treatment for low-grade brain tumors, mostly because
standard drugs cannot pass through the blood brain
barrier. Of some promise, researchers have identified
certain genetic arrangements in specific brain tumors
that make them sensitive to the effects of chemotherapy.
In general, however, chemotherapy is usually
administered in brain cancer as salvage therapy for
recurrent or slowly progressing cancers in patients who
have previously been treated. The role of chemotherapy
with brain cancers is constantly under investigation and
there are some promising studies.
Drugs Used in Chemotherapy
Carmustine (also called BCNU). Carmustine is
known as a nitrosourea. The response of gliomas to these
agents appears to depend upon certain genetic factors.
About 70% of gliomas have an enzyme (MGMT) that protects
against their actions. The other 30% are sensitive to
it. At this time, it is commonly used for glioblastoma
multiforme and to date, no agent has proved to be
superior for these tumors. Unfortunately, most patients
quickly develop resistance to the drug, so there have
been few improvements in survival rates with its use.
PCV and its Agents. The drug regimen called
PCV (procarbazine, CCNU, and vincristine) is effective
treatment for many common brain tumors. (CCNU is also
referred to as lomustine and, like carmustine above, is
a nitrosourea.) PCV has significant benefits for about
two-thirds of patients with oligodendrogliomas. It has
produced improvements in patients with anaplastic
astrocytoma and glioblastoma multiforme, but to date
does not appear to be any more effective than carmustine
for these tumors. This regimen has significant toxicity,
including suppression of red blood cell production and
cause nausea, vomiting, and weight loss. Patients must
adhere to certain dietary restrictions. Each of these
drugs is also used separately and in other combinations.
Temozolomide. Temozolomide (Temodal, Temodar),
the first drug to be approved for brain tumors in 20
years, is an oral agent that improves quality of life
and increases the time to progression for many patients
with recurrent malignant gliomas. It has been
specifically indicated for adult patients with
anaplastic astrocytoma that does not respond to other
treatments. It is showing promise for recurrent
high-grade gliomas, glioblastoma multiforme, anaplastic
oligodendrogliomas, and low-grade astrocytomas. It has
only modest and short-lived effects on recurrent gliomas.
It has few serious adverse effects and may even be
beneficial for elderly patients with glioblastoma who
have good performance status. It is being studied in
combination with other agents and with radiation
Other Chemotherapy Agents Used or Investigated for
Recurring or High-Grade Cancers
A number of drugs and treatments are being tested or
used for primary and recurring tumors.
- Tamoxifen, a breast-cancer drug, may also be
beneficial in a minority of patients with glioma
when administered continuously at high doses. More
research is needed to determine which patients may
- High-dose thiotepa along with bone marrow or stem
cell transplantation is being tested for newly
diagnosed aggressive oligodendroglioma as an
alternative to radiotherapy. Although some patients
have prolonged disease-free survival time, thiotepa
has very toxic side effects, including
encephalopathy (brain damage), liver damage, severe
weight loss, and a drop in blood platelet count.
High-dose thiotepa along with bone marrow or stem
cell transplantation is being investigated for
recurrent aggressive oligodendroglioma. [ See
Transplantation Procedures , below.]
- Paclitaxel (Taxol), a drug used for breast cancer,
is also being investigated for gliomas. It is
showing promise for patients with recurrent gliomas.
In one study, paclitaxel with stereotactic
radiosurgery improved results for patients with
- Topo I inhibitors block topoisomerase I, an enzyme
involved in cell replication. Clinical studies have
shown that the Topo I inhibitors topotecan and
irinotecan injure brain tumor cells. Combinations of
Topo I inhibitors with standard chemotherapy drugs,
such as BCNU, is proving to be effective for some
patients. Some studies suggest it may help some
children with gliomas. They may also be important
agents in radiochemotherapy. Less positive studies
on irinotecan report that combinations with
anti-seizure medications reduce its effectiveness.
- 5-fluorouracil (5-FU) is a standard chemotherapy
agent for a number of malignancies. It has not, to
date, been useful for brain tumors, because like
most of these agents, it cannot pass the blood brain
barrier. A new form (Ethypharm), however, employs a
microsphere containing the drug that is implanted in
the tissue. Early studies are promising.
Investigators are also looking at genetic therapies
to deliver the drug directly to the tumor.
- Carboplatin with or without vincristine is being
studied for low-grade progressive gliomas, which are
difficult to treat with surgery or radiation.
Side Effects of Chemotherapy
Because chemotherapeutic drugs may also affect normal
cells, side effects are common. To help offset these
effects, chemotherapy is given intermittently over a
scheduled period that allows normal cells to recover
between treatments. Side effects include nausea,
vomiting, fatigue, infection, bleeding, and hair loss.
In addition, the agents used to treat symptoms
(anti-seizure drugs, antidepressants, and
corticosteroids) may interfere with standard
chemotherapeutic agents. Specific drugs may have
different complications; for example, vincristine can
cause nerve injury and cisplatin may result in hearing
loss. Procarbazine requires dietary restrictions. Side
effects are almost always temporary and may be managed
with other medications.
Approaches to Enhance Drug Access to the Tumor
To make chemotherapy more effective, scientists are
working on a number of approaches to overcome an
obstacle unique to brain cancer: the blood-brain
barrier, a functional barrier that protects the brain
and prevents certain molecules from passing through.
- Certain drugs, such as mannitol or agents called
receptor-mediated permeabilizers, may open the
barrier without worsening neurological deficits.
- Interstitial chemotherapy uses disc-shaped wafers
(known as Gliadel wafers) soaked with carmustine,
the standard chemotherapeutic drug for brain cancer.
The physician places the wafer directly into the
surgical cavity after a tumor is removed. Studies
suggest that this approach can improve survival in
some patients. The procedure does not appear to
increase the risks of side effects over those of the
- Intrathecal infusion delivers chemotherapeutic
drugs directly into the spinal fluid.
- Intraarterial delivery administers high-dose
chemotherapy into arteries in the brain using tiny
catheters. In a 2000 study, this approach was used
within two weeks of radiotherapy in patients with
high-grade astrocytomas, and the survival rates for
glioblastoma multiforme tripled (20 months) compared
to those who had chemotherapy and radiation at the
- Enclosing highly potent anti-cancer drugs, such as
anthracyclines, in protective microspheres (called
liposomes) may allow the drugs time to enter tumors
without unduly increasing the risk for severe
toxicity. Such agents are not ordinarily used for
brain cancers because of high toxicity and poor
penetration of brain tumors.
- An investigative technique called
electrochemotherapy (ECT) applies high-voltage
pulses to deliver drugs across cancerous tissues,
including those of the brain.
WHAT ARE SOME INVESTIGATIVE THERAPIES USED FOR BRAIN
A number of drugs that target specific mechanisms
associated with brain cancer are being tested.
Combinations of some of these drugs with or without
standard chemotherapy and radiotherapy may prove to be
more effective than the use of any one treatment. It
should be noted that none of these drugs at this time
are producing cures, although some are improving
Immunotherapy aims at using modalities that boost the
patient's own immune system's ability to seek out and
destroy cancerous cells.
Radioimmunotherapy with Monoclonal Antibodies.
Radioimmunotherapy is showing special promise as a
treatment approach to brain tumors. It typically employs
monoclonal antibodies (MAbs), which are genetically
engineered antibodies designed to work against a
specific target. MAbs are bound with radioactive
substances and delivered directly into the brain and
sometimes into the tumor. The MAbs are specifically
designed to lock with the surface of certain cells in
the tumor. Once they do so, the radioactive substances
destroy the cell. The approach is essentially
mini-radiation therapy without the damage or severe side
effects of standard radiation treatments. A number of
different radioimmunotherapies are being investigated,
and trials of some are reporting improved survival rates
in high-grade gliomas. Some experts believe this
approach could prove to be the most effective therapy
against these cancers.
Interleukins. Interleukins are natural
proteins created by the immune system. Certain tumor
cells carry receptors for specific interleukins, which
are being investigated for a possible therapeutic role.
For example, some drugs combine an interleukin with an
agent that is toxic to cancer cells. The interleukin
locks onto the receptor on the cancer cell and the toxic
chemical enters the tumor with the intent to kill it.
Some interleukins are also being investigated alone for
their own tumor-cell killing properties.
Tumor Vaccines. Tumor vaccines are also being
created, in which tumor cells are removed from the
patient and inactivated; when they are transferred back
to the patient, they are harmless but can elicit a
powerful immunologic response against the tumor. For
example, a vaccine that combines tumor proteins with the
patient℮?s nerve cells is being tested in
Cell Growth and Angiogenesis Inhibitors
Much research is focusing on drugs that block small
molecules involved with the growth of blood vessels that
feed the tumor (a process called angiogenesis).
Such agents, when effective, would starve tumors of
vital nutrients and oxygen.Angiogenesis is particularly
important in the growth of glioblastomas, the most
malignant brain tumors. Of particular promise are agents
that inhibit enzymes called tyrosine kinase, farnesyl
protein transferase, and matrix metalloproteinase, which
play critical roles in angiogenesis.
Farnesyl Protein Transferase Inhibitors.
Farnesyl protein transferase inhibitors, such as
tipifarnib, also called R115777 (Zarnestra) and
lonafarnib (Sarasar), are drugs in a new class that
block a mutated gene called the Ras gene, which is
responsible for about 30% of cancers. Lonafarnib is in
early trials in combination with temozolomide.
Tipifarnib is also currently in early trials and may
prove be effective as radiosensitizer.
Tyrosine Kinase Inhibitors. Agents that target
receptors of growth factors, such as one called tyrosine
kinase, interfere with the pathway leading to
angiogenesis. Some tyrosine kinase inhibitors, including
erlotinib (Tarceva), imatinib (Gleevac), gefitinib (Iressa),
and others. are being investigated in early trials. Some
are showing specific promise as radiosensitizers. Side
effects include rash, diarrhea, nausea and vomiting.
Some may reduce white blood cell count or produce liver
Matrix metalloproteinase Inhibitors. Matrix
metalloproteinase is an important enzyme in angiogenesis.
Inhibitors of these enzymes, including marimastat,
metastat, and prinomastat, are in early trials.
Marimastat has been studied and has shown some benefits
in early trials for patients with recurrent glioblastoma
and anaplastic gliomas, particularly in combination with
Phophoinositide 3-Kinse (Pi3K) Inhibitors.
Rapamycin and its analog (CCI-779) inhibit Pi3K, an
enzyme involved in cell growth. Early trials using
CCI-779 are underway. (Another rapamycin analog,
everolimus, has different effects but is also being
studied for its actions in inhibiting cell growth.)
Other Drugs that Block Angiogenesis.
Thalidomide was one of the first drugs used to inhibit
angiogenesis and has undergone several trials. There is
some evidence that it may work more effectively for
metastasized brain tumors than primary tumors. Other
agents in early trials with various effects on tumor
growth include suramin, cilengitide, semaxanib, PTK787,
Other Investigative Agents
Retinoids. Retinoids are vitamin A derivatives
and act as differentiating agents in cancer
treatments. That is, they can convert immature, dividing
tumor cells into mature cells, stopping tumor growth.
Studies suggest that they have little benefits as single
agents. Combination with radiotherapy and other drugs
may hold promise.
Inactivated Viruses. Investigators are finding
that certain genetically inactivated viruses, such as
the poliovirus or herpesvirus, may prove to be valuable
fighters of brain cancers. Such viruses can enter cells
and destroy them but do not pose any danger for
infection. For example one specially designed herpes
virus targets the enzyme thymidine kinase (an enzyme
that promotes tumor growth). Some researchers believe
that a combination of this virus with retinoids may be
effective with few serious side effects. Other viruses
are being investigated. A drug based on this model is
years away, however.
Immunnotoxins. Agents called immunotoxins use
natural toxins to kill malignant brain cells.
Agents that employ diphtheria toxins, including
TransMID-107R and DAB(389)EGF), are the first
immunotoxins to show some promise. Clinical trials are
investigating them for gliomas and metastatic brain
cancers. Other toxins under investigation include
irofulven (a mushroom toxin) and chlorotoxin (a
substance derived from scorpions).
COX-2 Inhibitors. Celecoxib (Celebrex),
rofecoxib (Vioxx), and valdecoxib (Bextra) are known as
COX-2 (cyclooxygenase-2) inhibitors, or coxibs. They
inhibit an inflammation-promoting enzyme called COX-2.
Coxibs are commonly used to relieve pain, but they also
appear to have effects that inhibit tumor cell growth,
including gliomas. Such effects may be similar to
retinoids and trials are investigating combinations of
these two agents. The value of COX-2 inhibitors in the
treatment of patients with brain tumors is unknown.
Taurolidine. Taurolidine is a unique agent
that prevents tumor formation and growth in animals. An
early clinical trial in patients with high-grade gliomas
is under way.
Protein-Blocking Drug. Another development is
the discovery of a protein called BEHAB (Brain-Enriched
Hyaluronan Binding Protein). BEHAB is produced only by
invasive glioma tumor cells, not by normal brain tissue
or noninvasive tumor cells. Breakdown of BEHAB releases
a substance called HABD (hyaluronan-binding domain),
which appears to give glioma cells the ability to invade
other areas of the brain. Both BEHAB and HABD represent
potential targets for new therapies.
Transplantation Procedures and High-Dose
Chemotherapy destroys not only cancer cells, but also
healthy cells, including special blood cells in the bone
marrow called stem cells, which are immature cells from
which all blood cells develop. Transplantation
procedures using bone marrow or stem cells allow
high-dose chemotherapy to be administered while
protecting blood cells. The procedures are being tested
for patients with brain tumors that are responsive to
the effects of chemotherapy. A 2003 study, for example,
reported long-term survival in some patients, but it is
not clear if such rates are any better than other
treatments. The procedure has serious, sometimes
life-threatening, side effects.
Photodynamic therapy employs a special agent (Photofrin)
that is absorbed by the tumor and causes the cancer
cells to become fluorescent when a laser is directed at
them. It is being investigated in late-stage trials in
combination with other treatments. A 2003 study reported
encouraging results, notably with patients with
recurring glioblastoma multiforme. In the study, more
than half of these patients survived for at least a
WHAT ARE TREATMENTS FOR SOME COMPLICATIONS OF BRAIN
Some tumors, particularly medulloblastomas,
interfere with the flow of cerebrospinal fluid and cause
hydrocephalus. This causes a build-up fluid in the
ventricles (the cavities) in the brain. This can cause
nausea and vomiting, severe headaches, lethargy,
difficulty staying awake, seizures, visual impairment,
irritability, and tiredness.
Corticosteroids (commonly called steroids), such as
dexamethasone (Decadron), prednisolone, and prednisone
are used to treat hydrocephalus (fluid build up in the
brain). Side effects include high blood pressure, mood
swings, susceptibility to infection, increased appetite,
facial swelling, and fluid retention.
Human corticotropin-releasing factor (hCRF), a
naturally occurring neurohormone, appears to possess
substantial anti-swelling properties and thus has been
proposed as an alternative to corticosteroids in brain
edema, with potentially fewer side effects.
A shunt procedure may be performed to drain fluid.
Shunts are flexible tubes used to reroute and drain the
Seizures are common in brain tumor cases, with
younger patients having higher risks than older ones.
Anti-epileptic medications, such as carbamazepine or
phenobarbital, may used to treat seizures and are
helpful in preventing recurrence. These agents are not
useful in preventing a first seizure, however. It should
also be noted that anti-seizure medications might
interact with some of the chemotherapies used to treat
the brain cancers, including paclitaxel, irinotecan,
interferon, and retinoic acid. Patients should discuss
these interactions with their physician. [For more
information see the Well-Connected Report # 44, Epilepsy.]
Antidepressants are very useful for treating the
emotional side effects of this disease. Support groups
can also have great benefit for both patients and
families. [ See Where Else Can Help be Found for
WHERE ELSE CAN HELP BE OBTAINED FOR BRAIN TUMORS?
American Brain Tumor Association (www.abta.org
). Call 800-886-2282.
The Brain Tumor Society (www.cbtf.org
). Call 800-770-8287.
Brain Tumor Registry of the United States (www.cbtrus.org
Musella Foundation For Brain Tumors, Research &
Children's Brain Tumor Foundation (www.childrensneuronet.org
). Call 212-448-9494.
National Brain Tumor Foundation (www.braintumor.org
). Call 800-934-CURE.
American Association of Neurologic Surgeons (www.neurosurgery.org
). Call 888-566-2267.
American Cancer Society (www.cancer.org)
. Call 800-ACS-2345.
National Cancer Institute (http://cis.nci.nih.gov
). Call 800-422-6237.
The following site lists clinical trials http://cis.nci.nih.gov/resources/clinical.html
National Coalition of Cancer Survivors (www.cansearch.org).
Pediatric Oncology Group ( www.pog.ufl.edu
). Call 312-482-9944.
The International Radiosurgery support association (www.braintumor.org/pservices/csbtstereotatic.asp
The Candlelighters Childhood Cancer Foundation (www.candlelighters.org)
. Call 800-366-2223.
Pediatric Oncology Resource Center (http://www.acor.org/diseases/ped-onc/main.html)
University of Pennsylvania sponsors a cancer site at http://oncolink.upenn.edu/disease/melanoma
National Comprehensive Cancer Network (www.nccn.org)
American Society for Clinical Oncology (www.asco.org)
Anatomy of the Brain (www.waiting.com/brainanatomy.html)
Family members of patients with neurologic problems
can find information at www.waiting.com
Find a Neurologist at www.aan.com/rostersearch_f.html
Find a Neurosurgeon at www.neurosurgery.org/health/findaneurosurgeon.html
Review Date: 8/22/2003
Reviewed By: Harvey Simon, MD, Editor-in-Chief,
Associate Professor of Medicine, Harvard Medical School;
Physician, Massachusetts General Hospital. Stephen A.
Cannistra, MD, Oncology, Associate Professor of
Medicine, Harvard Medical School; Director, Gynecologic
Medical Oncology, Beth Israel Deaconess Medical Center.
The information provided herein should not be used
during any medical emergency or for the diagnosis or
treatment of any medical condition. A licensed physician
should be consulted for diagnosis and treatment of any
and all medical conditions. Call 911 for all medical
emergencies. Links to other sites are provided for
information only -- they do not constitute endorsements
of those other sites. Copyright 2003 A.D.A.M., Inc. Any
duplication or distribution of the information contained
herein is strictly prohibited.