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Classifications of brain tumors
Brain tumors are classified as primary or secondary. Primary brain tumors
are brain tumors that grow from the brain tissue or its immediate surroundings.
Secondary, or metastatic, brain tumors are tumors that start in another part of
the body, such as the breast or lung, and travel to the brain, usually by way of
the bloodstream.
Primary brain tumors can be non-cancerous (benign) or cancerous (malignant).
All secondary brain tumors are, by definition, cancerous. Secondary brain tumors
are more common than primary brain tumors.
Primary brain tumors
Common benign primary brain tumors include those of the lining of the skull
(meningiomas), those of the nerves (schwannomas) and those of the pituitary
gland (pituitary adenomas). However, it's important to recognize some features
of benign primary brain tumors. First, benign brain tumors can become malignant.
Second, once removed, benign tumors can also re-grow, unless nearly every tumor
cell was destroyed or removed during treatment.
Today, with few exceptions, most primary brain tumors involving the brain
tissue (gliomas) are considered cancerous. These cancers can range from slow
growing, non-invasive tumors (low-grade tumors) to rapidly-growing, highly
destructive tumors (high-grade tumors) such as glioblastomas. In the past, many
practitioners incorrectly referred to the low-grade tumors as being benign. It
is now widely recognized that even these low-grade tumors are rarely cured and
usually change into higher-grade tumors over time.
Although the outlook for patients with gliomas has not changed much since the
1960s, selected treatments have been shown to benefit specific groups of
patients. A variety of promising investigational approaches also might lead to new
treatments in the near future.
Secondary brain tumors
Nearly one in four people with cancer will get a malignant brain tumor.
Traditionally, the prognosis for patients with these tumors was bleak; people
were expected to survive only several weeks after diagnosis. More aggressive
surgical treatments, innovative radiation approaches, and new approaches to
chemotherapy now lead to good quality survival that is measured in months to
years.
Pediatric brain tumors
Brain tumors in children often arise from tissues that are different from
those most commonly affected in adults. In addition, some of the treatments that
are tolerated by an adult's brain can prevent normal development of a child's
brain.
Common pediatric tumors include tumors of primitive cells that have not
matured into adult cell types (primitive neuroectodermal tumors or "PNETs"),
tumors of the lining of the brain's fluid sacs (ependymomas), and benign tumors
of the supporting cells of the brain (juvenile astrocytomas).
The origins of brain tumors
It is thought that a brain tumor occurs when certain genes on the
chromosomes of a cell become damaged and can no longer function properly. These
genes normally regulate how often the cell divides (or if it divides at all) and
repair genes that fix defects of other genes. Among the genes they fix are those
that tell a damaged cell that cannot repair itself to self-destruct.
Some people might be born with partial defects in one or more of these genes
and environmental factors might lead to further damage. In other people,
environmental factors might be the only cause of damage to the genes.
Once a cell is dividing too rapidly and cannot check its own growth, it can
grow into a tumor. If a tumor cell begins to grow, the body's immune system
should detect the abnormal cell and kill it. Many tumors, however, produce
substances that block the immune system from recognizing the abnormal tumor
cells. Over time, the tumor cells overpower all of the body's defenses against
their growth.
As with other cells, tumor cells need oxygen and nutrients to survive. Cells
normally receive nourishment from blood brought to the tissues by blood vessels.
However, a rapidly growing tumor might need more oxygen and nutrients than the
nearby blood vessels can provide. In response, tumors produce substances called
"angiogenic factors," which stimulate the growth of new blood vessels
(angiogenesis). These new blood vessels increase the supply of nutrients to the
tumor. Eventually, the tumor depends on the new blood vessels to survive.
Brain tumor treatment and management
The main treatments for brain tumor are surgery, radiation, and chemotherapy
alone or in combination. New surgical and radiation techniques that lessen the
risk and discomfort associated with traditional brain surgery are also
available. These procedures might allow patients with primary brain tumors to
avoid or postpone surgery and often produce results similar to those expected
from traditional surgery.
Surgery
Surgical removal of most or all of the tumor is the most common treatment.
The surgeon's challenge is to remove as much of the tumor as he or she can
without injuring normal brain tissue that controls the patient's normal
functions such speaking, walking, and using the hands.
In the past, surgeons made large openings in the skull (craniotomies) in
order to reach the tumor. Once the tumor was visible, the surgeon would look for
subtle differences in the appearance of the normal tissue and the tumor and use
these differences to guide him or her in how much of the tissue to remove.
Exploration was common and frequently resulted in complications.
In the early 1990s, computerized devices called surgical navigation systems
were developed. These devices enable the surgeon to more accurately determine
the size, location, and position of the tumor. They have greatly reduced the
risk of complications from surgery and have allowed surgeons to remove some
tumors that were once considered inoperable.
In the late 1980s, researchers invented
one of these navigational systems. In addition to guiding open craniotomy, this
surgical navigational system can also be used to guide brain biopsy, the removal
of a small piece of tissue for testing.
One limitation of these systems is that they use scans (computed tomography,
magnetic resonance imaging), electronic pictures of the brain, obtained prior to
surgery to guide the surgeon. However, these scans cannot account for movements
of the brain that occur during surgery. Investigators are
developing ways of using ultrasound and even performing surgery within an MRI
scanner device to help update data from the navigation system during surgery.
Radiation
The aim of radiation treatments when applied to brain tumors is to
selectively kill the tumor while leaving normal tissue (often mixed with the
tumor cells) unharmed. This may be accomplished in two ways.
Traditionally, multiple treatments of low-dose radiation are applied to the
tissue. Each treatment damages both healthy and cancerous tissue. By the time
the next treatment is given, most of the normal cells have repaired the damage
while the tumor cells have not. This treatment is repeated 10 to 30 times,
depending on the type of tumor. Ideally, 98 percent of the tumor will be killed and 98
percent
of the normal tissue will survive.
Researchers think that the process that kills the tumor cells is one in which
the cell recognizes unrepairable damage and self-destructs. Unfortunately, this
mechanism is not intact in all tumor cells, and even if it is, the remaining
tumor cells usually re-grow, especially if the tumor was large.
Gamma knife radiosurgery
Another way to selectively kill tumor cells while sparing normal tissue is
to focus an intense dose of radiation directly at the tumor. This treatment,
called "radiosurgery," uses computers and devices such as the Gamma
Knife.
Just as a magnifying glass can focus sunlight to a point of intense heat
while the rest of the area under the glass remains cool, these devices deliver
highly focused doses of radiation to the target area. Computers help match the
shape of the radiation to the shape of the tumor (conformal radiosurgery).
Unfortunately, a single radiosurgery treatment can only be used to treat
tumors of a limited size since larger tumors require defocusing the radiation.
The wider the area needing treatment the less targeted the dose of radiation
will be. Nonetheless, radiosurgery is a very effective treatment for many benign
and malignant tumors and can be used instead of conventional radiation or
surgery or in combination with these treatments.
Peacock-and Novalis fractionated radiosurgery
Recently, devices that take advantage of both means of treating the tumor
while sparing normal tissue have been invented. The Peacock and Novalis devices
focus radiation over a few or many sessions, while matching the shape of
delivered radiation to the tumor, allowing larger tumors to be safely and
effectively treated than can be managed with devices such as the Gamma Knife.
Chemotherapy
Chemotherapy is the treatment of disease with chemicals or drugs. It works
by causing cell damage that is better repaired by normal tissue than by tumor
tissue. Chemotherapy has had a checkered history in the management of brain
tumors. It is clearly effective in certain pediatric tumors, lymphomas, and
oligodendrogliomas. Certain tests might predict response to chemotherapy for
certain tumors.
Although it has been proven that chemotherapy improves survival rates in
patients with the most malignant of primary brain tumors, it does so in only a
fraction of the patients (about 20 percent). Which patients will benefit also cannot be
readily predicted beforehand. As such, many patients (and their doctord)
choose not to use chemotherapy because of its potential side effects (lung
scarring, suppression of the immune system, nausea, and so forth).
Brain tumor cells might resist chemotherapy because they have abnormal
mechanisms for detecting cell damage. Or, the chemicals used in chemotherapy might
be unable to pass from the bloodstream into the brain because of a special
barrier between the blood vessels and the brain tissue (blood-brain barrier).
Some investigators have tried to improve the effect of chemotherapy by
disrupting this barrier, but results have not been impressive.
Recently, new ways of delivering chemotherapy directly into tumor tissue have
allowed patients to receive chemotherapy without the systemic (whole-body) side
effects. Gliadel wafers applied on the tumor at surgery slowly secrete
chemotherapy into the tumor. Investigational injection of chemotherapy is also
being used in some cases.
Drugs that are not aimed at killing the cells, but rather at blocking growth,
have also been used. These growth modifiers, such as tamoxifen citrate (Nolvadex),
have been shown to stop or shrink some primary tumors that resist other
treatments. New drugs in this class are actively under development. Other drugs
that alter cell regulation include "small molecule" agents such as
Tarceva (OSI-774)
Immunotherapy
In theory, the body's immune system should recognize tumor cells as abnormal,
and then attack and destroy them. This immune surveillance probably occurs daily
and destroys many early tumor cells. A tumor cell might develop, however, that can
fool the immune system by making substances that block the signals that tell the
immune system to seek and destroy the abnormal cells. Or, the body's immune
system might be weakened by HIV infection, drugs, or alcoholism and allow tumor
cells to escape control.
Animal studies have shown that a healthy immune system that is being fooled
by the tumor can be taught to recognize the tumor and resume its control duties.
Researchers have
been working on a brain tumor vaccine that teaches the patient's immune system
to attack its previously cloaked primary tumor.
Immunotherapy represents a promising new class of treatments that, in theory,
could confer lifelong immunity to a variety of tumors affecting the brain. Other
promising means of using the immune system to treat tumors include tagging
potent toxins to antibodies that selectively seek out the tumor cell, thereby
poisoning only the tumor cells, delivered through slow, continuous infusion over
several days. This process is called convection-enhanced delivery.
Antiangiogenesis
Many tumors produce substances that promote the growth of new blood vessels
to help provide oxygen and nutrients for their nearly insatiable needs.
Eventually, these tumor cells become dependent on these new vessels. A promising
new technique is to use substances (antiangiogenesis factors) that inhibit these
blood vessels, thereby starving the tumor cells. These factors can obliterate
certain malignant tumors in mice, although they have not been used in humans.
Recent reports have suggested that these drugs might lead to a cure of cancer
within two years. Although this predication might prove to be true for some tumor
types, primary brain tumors are, unfortunately, composed of cells that are
metabolically voracious and cells that have much more modest requirements. Antiangiogenesis treatment, if it works, might only turn high-grade tumors into
lower-grade ones. Furthermore, there are situations in which production of new
blood vessels is important for health. The role of antiangiogenesis factors in
humans is promising but remains to be defined.
Gene therapy
Perhaps the most appealing means of curing brain tumors is to correct the
underlying defects in the genes that lead to tumor control. Genes that promote
growth could be turned off, those that suppress growth could be turned on,
defective monitoring mechanisms could be turned on, genes that produce a beacon
for the immune system could be delivered, and so on. Gene therapy has been used
successfully in mice to rid them of primary and secondary tumors. The principal
problem with gene therapy as the primary treatment of brain tumors is that, in
theory, every tumor cell must be treated with gene therapy. If even one cell
escapes, it could regrow into a large tumor.
While it is possible to inject enough reparative genes into a tumor in a
mouse to eradicate the tumor, it is quite a different thing to inject enough
gene therapy into a human brain tumor, which is likely to be much larger. To
date gene therapy has been shown to kill human tumor cells, unfortunately,
current delivery mechanisms are inefficient and unable to deliver enough to cure
the whole tumor. Nonetheless, gene therapy might well become an important future
treatment of human brain tumors, alone or in combination with the above
therapies.
Summary
Ground breaking new treatments are at hand for the treatment of many benign
and malignant brain tumors. Although it is unlikely that any one therapy will
cure primary brain tumors in the near future, combination treatments promise to
improve the outcome while lowering the side effects of treatment.
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