Glioblastoma multiforme = grade 4 astrocytoma

http://brain.mgh.harvard.edu/PatientGuide.htm
Glioblastoma multiforme and anaplastic gliomas: A patient guide

   by John W. Henson, M.D., MGH Brain Tumor Center

Astrocytomas and oligodendrogliomas are the most common primary tumors of
the adult brain. Both tumors are types of gliomas. Primary brain tumors
arise from cells of the brain itself rather than traveling, or
metastasizing, to the brain from another location in the body. Gliomas can
be slowly growing (low-grade, grades 1 and 2), or rapidly growing
(high-grade, grades 3 and 4). This material will give important facts
about the diagnosis and treatment of high-grade gliomas.

High-grade gliomas are diagnosed by a biopsy

Once a brain tumor is detected on a CT or MRI scan, a neurosurgeon obtains
tumor tissue for examination by a neuropathologist (a biopsy). The
neuropathologist then gives the tumor a name and grade. The exact name and
grade of the tumor determine treatment options, and also give important
information about prognosis.

When neuropathologists analyze tumor tissue under a microscope, there are
two main questions being asked:

   -first, what type of brain cell did the tumor arise from? The answer
to this question gives the tumor a name, for example, astrocytoma.

   -second, do the tumor cells show signs of rapid growth? This involves
assigning the tumor a grade, such as grade 3 or 4 (see below).

These two pieces of information are then combined, as in "grade 4
astrocytoma". Once a tumor has been given a name and a grade, brain tumor
specialists can give advice about treatment choices, prognosis, and
provide useful health-care information to brain tumor patients and their
families.

Tumor name: from what type of brain cell did the tumor arise?

Astrocytomas arise from brain cells called astrocytes. Normal astrocytes
are star-shaped cells that give the brain its shape. Astrocytes are the
most common cell type to become tumors. Oligodendrocytes are brain cells
that provide insulation around the electrically-active neurons. Tumors of
oligodendrocytes are less common than astrocytomas. Many tumors contain a
mixture of astrocytoma and oligodendroglioma cells. Tumors of other cell
types in the brain are less common. For instance, tumors of neurons are
very rare in adults.

Tumor grade: how aggressive does the tumor appear under the microscope?

Astrocytomas and oligodendrogliomas come in four grades, with grade 1
being the most benign and grade 4 being the most malignant. The
neuropathologist looks at the brain tumor tissue under the microscope for
signs that the tumor is growing rapidly. Examples of these features
include cells undergoing division (mitosis), the presence of newly-formed
blood vessels, and evidence that the tumor is outgrowing its blood supply
(necrosis). The more features that are present, the higher the grade
assigned to the tumor.

Gliomas have more than one name in everyday usage. The Table gives the
common names of high-grade gliomas:

Synonyms for high-grade Gliomas

Anaplastic astrocytoma = grade 3 astrocytoma

Glioblastoma multiforme = grade 4 astrocytoma

Anaplastic oligodendroglioma = grade 3 oligodendroglioma
(oligodendrocytoma)

Anaplastic oligoastrocytoma = grade 3 oligoastrocytoma = anaplastic mixed
glioma

Why do brain tumors occur?

Tumors form because of the abnormal, unregulated growth of cells. After
the human brain completes it development soon after birth, the vast
majority of its cells enter a resting state in which they never divide
again. One exception to this rule is when a brain tumor develops. The
abnormal brain cells re-enter the "cell-cycle" because of alterations in
any of a large number of genes that control cell division and growth.
Although much is known about the alterations in these genes in brain
tumors, the reason why the gene alterations arise in the first place is
poorly understood. The MGH has a very active research program in this
area.

Are brain tumors hereditary?

The use of the word ‘gene’ invariably brings up the important question of
whether brain tumors are hereditary. The answer for almost all patients is
no. Although there are conditions in which brain tumors can occur in
families, these syndromes are very rare and usually known prior to the
development of an individual family member’s tumor. Syndromes that include
an inherited risk of glial brain tumors include neurofibromatosis type I,
Turcot’s syndrome, and Li-Fraumeni syndrome.

Types of therapy

There are three standard types of treatment for patients with high-grade
gliomas: surgery, radiation therapy, and chemotherapy. In addition to
these standard therapies, major centers such as the MGH Brain Tumor Center
may offer experimental treatments.

Because grade 3 and 4 tumors have a tendency to grow rapidly, treatment
must be started as soon after surgery as is feasible, allowing time for
the surgical incision to heal. Generally, this means that patients should
be undergoing either radiation therapy or chemotherapy within 2 to 4 weeks
after surgery. An algorithm that is commonly used for treatment of
high-grade gliomas is presented on the following page.

While therapies for high-grade gliomas are helpful, at present these
treatments cannot cure these tumors. The two major reasons for this are
that tumor cells infiltrate into surrounding brain and thus cannot be
completely removed by the surgeon, and that most glioma cells are at least
partially resistant to radiation and chemotherapy.

The goals of treatment are to:

   -remove as many tumor cells as possible (with surgery)
   -kill as many as possible of the cells left behind (with radiation and
chemotherapy)
   -put remaining tumor cells into a nondividing, sleeping state for as
long as possible (with radiation and chemotherapy)

High-grade glioma cells almost always start to grow again at some point in
time. Patients receive aggressive treatment in order to delay this
regrowth as long as possible. Regrowth does not necessarily imply loss of
control of the tumor, but it does mean that a new series of treatments
should be considered because the tumor is becoming more aggressive.

Surgery

The first step in therapy is maximal feasible removal of tumor tissue.
Surgeons believe that patients with smaller amounts of tumor when they
start other treatments will have a better prognosis. Also, radiation
therapy is more easily tolerated when the pressure from the tumor can be
reduced.

There is great variability in the amount of tumor that can be safely
removed from the brain of a patient. The variability is based mainly on
the location of the tumor. For instance, tumors in some brain areas can be
removed with very low risk, while in other brain areas surgery is too
risky to contemplate. The decision about the benefit and risk of surgical
removal is one that experienced brain tumor neurosurgeons make every day.
The underlying principle is that the surgery should not worsen the
patient’s condition. The goal is for the patient to be the same or better
after recovering from brain tumor removal. When a tumor is located in a
sensitive area of the brain, a biopsy is performed with a small needle,
thereby avoiding further damage to brain function. It is important to
remember that gliomas infiltrate into surrounding brain, making complete
removal impossible in almost every case.

With modern neuro-imaging techniques such as MRI scans, it is possible for
doctors to have a high level of confidence that a brain tumor is present
prior to biopsy. In that case, it is safe to perform a major surgical
resection at the same time as obtaining tumor tissue for the pathologist
to examine. In some cases, however, it is necessary to perform a needle
biopsy first, and later proceed to a full-scale surgery.

A preliminary diagnosis ("frozen section diagnosis") is made by the
neuropathologist during the surgery in order to help the neurosurgeon know
what type of tumor is present. The patient and their family are informed
of this preliminary diagnosis immediately after surgery. However, further
recommendations about treatment are not made until the final pathology
report is available. The final report requires a minimum of 2 working days
after surgery. In difficult cases, the final report can take a week. It is
not uncommon for small, but important, changes to be made in the diagnosis
once all of the biopsy sections have been examined.

An MRI scan is usually obtained within 3 days after tumor removal. This
"post-op" MRI serves as a baseline for future comparison.

Radiation therapy

Radiation therapy is an important part of the treatment of high-grade
gliomas. In typical situations, patients begin radiation treatments within
2 to 4 weeks after tumor resection. A physician who supervises radiation
treatments is called a radiation oncologist.

Following a "simulation" session in which the radiation oncologist plans
the shape of the radiation beam as well as dose, treatments are given
daily, Monday through Friday, for 4 to 6 weeks. Each treatment takes only
a few minutes. During radiation, patients are seen weekly by the radiation
oncologist, and a nurse is available for questions every day. Most
patients feel better during radiation therapy if they are taking a small
dose of a steroid which reduces brain swelling, called Decadron (also
called dexamethasone).

There are usually no immediate side effects during each treatment. As the
treatment progresses, hair loss will occur over the area where the
radiation beam passes into the tumor. Most patients experience some
fatigue by the second or third week. For many, a 30 minute nap is helpful
every afternoon. There are a number of long-term side effects from
radiation therapy, ranging from those that are a minor nuisance to ones
that can produce major health problems. Fortunately, serious side effects
are rare. Furthermore, the potential risks of radiation therapy are
outweighed by the known risk of not treating the tumor. The radiation
oncologist will describe these risks prior to starting therapy.

An MRI is usually obtained about 2 to 4 weeks after the end of radiation
therapy in order to judge the effect of treatment. Most of the time this
scan will show no change from the post-operative MRI, which is good. Some
shrinkage is even better. Growth during radiation therapy is an unwanted
sign of an aggressive tumor.

Chemotherapy

Chemotherapy is helpful in controlling the growth of high-grade gliomas.
Several different types of chemotherapy drugs are available. A
neuro-oncologist is skilled at recommending these treatments. For most
tumors radiation is given prior to consideration of chemotherapy, however,
chemotherapy is often administered prior to radiation therapy for patients
with anaplastic oligodendrogliomas.

Chemotherapy for glioblastoma multiforme raises an important question as
to timing. Although chemotherapy is beneficial, it is not known whether
the timing of administration is important. Many centers in the United
States now save chemotherapy until there is evidence that the tumor is
growing after radiation therapy. This may mean that months or even years
could elapse between radiation and chemotherapy. Other specialists prefer
to give chemotherapy immediately after radiation therapy and to give
different chemotherapy when the tumor starts to grow again. This decision
has to made on a patient-by-patient basis.

In addition to standard chemotherapy, there are studies of new drugs which
are conducted in major research centers. It is usually good to enter a
research study if eligible, both for reasons of personal benefit and for
the benefit of others in the future. Neuro-oncologists will provide
information about clinical trials.

The possible side effects of chemotherapy will be discussed before
beginning treatment. Today, chemotherapy is much less toxic than even a
few years ago. Although chemotherapy is targeted against dividing tumor
cells, there are normal cells in the body which are also dividing. These
normal cells can also be temporarily affected by chemotherapy and may lead
to side effects. Specifically, the cells which can be affected are those
in the bone marrow and the cells which line the gastrointestinal tract.
The cells in the bone marrow form the blood cells that are circulating in
the body. These cells include white blood cells which fight infection, red
blood cells which carry oxygen, and platelets which prevent bleeding.

Two other types of cells which may be affected temporarily or permanently
are the female egg cells and those cells which produce sperm in the man.
In men, chemotherapy can cause sterility, and therefore may make men
unable to father a child. Men should discuss this with the doctor before
starting chemotherapy.

Women of child-bearing years need to use a reliable birth control method
for the entire time, including the rest periods, when receiving
chemotherapy. Men should use a condom when having sexual relations within
3 days of getting chemotherapy to protect their spouses from exposure to
the drug. The effects of many chemotherapy drugs can be harmful to the
growth and development of a fetus, therefore it is crucial to not become
pregnant or father a child while receiving chemotherapy.

When receiving chemotherapy, and for 3 days after, it is important that
careful attention be paid to hand washing after urination. Since many
chemotherapy drugs are removed from the body by the urine, careful hand
washing will prevent family members from being exposed to the
chemotherapy. If family members help with personal care of the patient,
they should wear rubber gloves when handling urine or vomitus. Clothing
soiled with urine, vomit, or feces should be washed separately in hot
soapy water.

After treatment is completed

Once the recommended treatments have been completed, an observation phase
is entered. In the observation period, visits to the neuro-oncologist
occur every 2 to 4 months. At these visits there is a review of symptoms,
medications, physical condition, and usually a surveillance MRI or CT is
obtained.

Regrowth of tumor

Surveillance and careful follow-up are necessary because of the harsh
reality that high-grade gliomas have a well-known tendency to regrow. Most
often, regrowth occurs at the same site where the tumor arose. If and when
tumor progression is discovered, brain tumor specialists may recommend
further surgery, radiation, or chemotherapy.

Prognosis

The prognosis is different for each of the tumors discussed in this
booklet. The specialists will discuss prognosis with you.

Practical Advice

Leaving the hospital after surgery

Most patients recover very quickly after surgery on their brain tumor. The
majority are able to leave the hospital within a few days. Some patients
go directly home, whereas others benefit from inpatient stay in a
rehabilitation hospital to optimize physical function and to gain strength
prior to going home. The neuro-surgeon will remove the sutures 7 - 14 days
after surgery. The head should be kept dry until the sutures have been
removed.

On the last page of the booklet, there is a check list to complete before
leaving the hospital. It is important to meet the doctors who will be part
of the team of brain tumor specialists. There are three kinds of brain
tumor specialists:

   -Neurosurgeon

   -Radiation oncologist

   -Neuro-oncologist

Sometimes it is not possible to see all three specialists in the hospital,
in which case their names, telephone numbers, and an appointment date will
be provided prior to discharge. Also plan to see a primary care doctor
soon after discharge. This doctor will be an important resource for
general medical problems, should they arise.

Keep permanent notes in a notebook

There will be many discussions with doctors and nurses about symptoms,
test results, treatments, and medications. It is helpful to keep careful
notes and dates in a permanent book like a college notebook or a diary.

Side-effects of common medications

Decadron: Decadron (dexamethasone) is very useful to reduce swelling
around the tumor. It also has many side effects, but these are usually
less important that the benefit from taking Decadron. However, it is
always a major goal find the smallest dose that is helpful. Side effects
include: euphoria, with excessive feeling of well-being and insomnia;
increased appetite, especially for sweets; weight gain with fat deposition
in the cheeks; high blood sugar, particularly in diabetics; high blood
pressure; muscle weakness in the legs (this affects climbing stairs and
arising from chairs); stomach ulcers (an acid blocking drug is usually
given to combat this); and increased risk of infection (patients on
Decadron for more than 2 months should ask about prophylactic Bactrim). It
is not necessary to check blood levels of Decadron.

Dilantin: Dilantin (phenytoin) is a common medication taken to prevent
seizures. The major side effects of Dilantin are toxic blood levels (too
high), and rash. Dilantin toxicity causes clumsiness while walking, much
like that of alcohol intoxication. Dilantin rashes are very common and can
be dangerous so that the patient must quickly switch to a different
medication for seizure control. (Note: changing a seizure medication
requires consultation with a neurologist or neuro-oncologist). Some
patients experience fatigue with Dilantin, but this symptom is more
commonly due to the tumor and its treatment.

Tegretol: Tegretol (carbamazepine) is a common anti-seizure medication. It
may cause a rash, may lower the white blood counts, and often causes
double vision when levels become toxic.

Depakote: Depakote (valproic acid) is another common anti-seizure
medication. The most frequent side effect is a mild tremor in the hands.
The liver can be injured by this medication. A rash is much rarer than
with Dilantin. This medication is very harmful to the human fetus and
cannot be given to pregnant women.

Primary care doctor

It is important to identify and keep in touch with a primary care doctor
or family physician. Remember to ask each specialist to send copies of all
letters and notes to the primary care doctor. The primary care doctor
should be contacted for many issues that will come up with general health
and insurance matters. For questions about surgery, radiation, and
chemotherapy, and medications for the tumor, the specialists should be
contacted by the primary care doctor or by the patient and family.

When to call the specialist

You should call the specialist in the following situations:

   -After a seizure (see below).

   -Severe headache or abrupt worsening of existing neurological
problems.

   -Swelling of the ankles and legs, particularly if the swelling is
worse in one leg than in the other. This may indicate the presence of a
blood clot in the large veins of the legs (this is called deep venous
thrombosis, or DVT). The risk of DVT is quite high in patients with brain
tumors. DVTs are dangerous because the clots can break off and travel to
the lungs. Blood thinner pills are usually required after diagnosis of a
DVT.

   -Signs of infection—fever, chills, pain on urinating, unusual
headache, stiff neck, sore throat, or severe abdominal pain.

   -Signs of possible bleeding—unusual bruising, severe headache, unusual
abdominal pain, bright red blood from the nose or rectum.

   -Severe nausea and vomiting.

   -A skin rash.

These are some of the situations in which a doctor needs to be contacted.
Sometimes it is hard to know whether to call the doctor about a certain
problem. If unsure, it is safest to call. Telephone numbers of the doctor
and a number at which the doctor on call can be reached after hours or on
weekends should be kept available.

Seizures

Seizures may occur in patients with brain tumors. Seizures can have many
different manifestations, but common types are twitching of the face, arm
or leg without complete loss of consciousness, and total body shaking with
complete loss of consciousness.

Most seizures are brief and self-limited. If a seizure lasts for 2 minutes
or less and the patient returns to normal quickly, make a telephone call
to the neuro-oncologist at the Brain Tumor Center (617-724-8770) for
instructions (for example, to check the blood level of a seizure
medication). If the seizure lasts for more than 3 minutes or if a second
seizure occurs, it is usually necessary to call for medical help by
dialing 911. Have the doctor at the Emergency Room call the Brain Tumor
Center for advice.

In patients with seizures, the following activities should be discussed
with a neuro-oncologist: driving, operating heavy equipment, swimming, any
potentially dangerous activity.

In the event of a seizure, four things are important:

   -do not put anything in the patient’s mouth

   -protect the patient from sharp objects or dangerous situations during
the seizure

   -if vomiting occurs, turn the patient on their side to minimize the
risk of aspiration

   -remain calm and call for help. Patients do not suffocate during
seizures.

Self help at home

There are some important things to do at home. These include:

   -keep a positive mental attitude.

   -take medications faithfully and as prescribed. Pharmacies sell pill
organizers which can help as a memory aid

   -keep a written, up-to-date list of medications for review at home or
at the doctor’s office.

   -eat a healthy diet—including plenty of fresh fruits, fruit juices and
vegetables to prevent constipation.

   -take 1 multivitamin with iron each day.

   -get some form of exercise-- even a little is better than none.
However, avoid exhaustion.

   -no change in usual sexual activity is necessary. Contraception is
very important.

   -avoid alcohol. Some specialists allow patients to take small amounts
of alcohol on occasion, but since alcohol impairs brain function and can
worsen the side-effects of medications, the safest policy is to stay away
from it altogether.

   -be alert to signs of infection or bleeding.

Returning to work

Neuro-Oncology Service. This inpatient service is under the leadership of
the Brain Tumor Center neuro-oncologists (the "attending"), who is
assisted by a neuro-oncology "fellow", neurology residents, and specialist
nurses. Physical and occup-ational therapists usually help with exercises.
A case manager helps to make plans for discharge to home, rehabilitation,
or other location.

The attending neuro-oncologist working on the inpatient service upon
admission may not be the patient’s primary neuro-oncologist, since the
hospital attendings rotate at the beginning of each month. However, all
major decisions will be made in conjunction with the primary
neuro-oncologist’s advice. The primary neuro-oncologist will make frequent
visits to check on the overall progress during the hospitalization.

Neuro-Oncology Fellows and Nurse Practitioners

The MGH Brain Tumor Center has a training program for new brain tumor
specialists. These "fellows" are fully-trained physicians who are
specialists in neurology, neurosurgery, or medical oncology, and who are
taking advanced education in neuro-oncology. The fellows will be helpful
with all aspects of treatment and follow-up. Similarly, the MGH Brain
Tumor Center has nurse practitioners who work with the attendings and
fellows to provide patients with the best possible care.

Physical Therapy and Rehabilitation

During a hospital admission, a physical therapist may be consulted to
assess your functional status and provide treatment aimed at maximizing
your independence and functional capacity. Upon discharge, home or
out-patient physical therapy may be recommended to continue to maximize
your functional mobility. If you require more intensive physical therapy,
you may benefit from an inpatient stay at a rehabilitation hospital.
Physical therapy evaluation includes identifying what areas may be
limiting your function: strength, balance, endurance, pain. The physical
therapist may prescribe individualized exercises to address the above
areas, and may recommend adaptive equipment.

Occupational Therapy

Occupational therapy (OT) is the therapeutic use of self care, work, and
leisure activities to increase independent function and prevent
disability. It includes adapting tasks and the environment to maximize an
individual’s independence and quality of life. An occupational therapist
can assess level of function in activities of daily living (ADLs), taking
into account physical, cognitive and perceptual abilities as they
influence performance of these tasks. An occupational therapist can give
instruction in the use of assistive devices, adaptive techniques and hand
splints (as necessary) to increase independence in day-to-day tasks.
Occupational therapists evaluate and treat individuals in the hospital
unit, at home. The outpatient service is located at ACC 127. Following a
physician referral for outpatient OT, call (617) 724-6575 to schedule an
appointment.

Social Service

Clinical social workers are licensed professionals trained to help people
find solutions to many emotional problems-- from daily crises to life's
most difficult situations. This is accomplished through a unique
combination of counseling, active problem solving and direct connection
with the network of community and hospital resources. To speak with a
social worker, simply ask a nurse or physician, or call the Social Service
Department at (617) 726-2643 or (617) 726- 5841 (outpatient).

The Cancer Resource Room (on the first floor of the Cox Building) is an
important resource at the MGH. It is a place where patients and families
can find information about everything from treatment modalities to coping
to talking with one's children. Another helpful resource is the Brain
Tumor Support Group which meets in the Brain Tumor Center the 1st and 3rd
Tuesdays of the month from 12:00-1:30 PM. The group offers an opportunity
for patients and family members to learn about the issues that concern
them most as well as an opportunity to meet others living with similar
experiences. For more information call (617) 726-5841.

Education at home

Information about brain tumors is available from home on the world wide
web. Here are some useful web sites to visit:

MGH Brain Tumor Center (617) 724-8770 http://brain.mgh.harvard.edu/

Brain Tumor Society (800) 770-8287 http://www.tbts.org/

American Brain Tumor Association (800) 886-2282 http://www.abta.org/

DISCHARGE CHECKLIST

Diagnosis: _________________________________________________________

Date of diagnosis:
_________________________________________________________

Neuro-oncologist:
_________________________________________________________

Name:  _________________________________________________________

Telephone:  _________________________________________________________

Appointment:  _________________________________________________________

Radiation oncologist:
_________________________________________________________

Name:  _________________________________________________________

Telephone:  _________________________________________________________

Appointment:  _________________________________________________________

Neurosurgeon:  _________________________________________________________

Name:  _________________________________________________________

Telephone:  _________________________________________________________

Appointment:  _________________________________________________________

Name of the doctor to contact in case of an urgent question. (Suggestions
about when to call a specialist are presented above).
_________________________________________________________

List of medications, and prescriptions.
_________________________________________________________

Ask about driving.
_________________________________________________________

Know what to do in case of a seizure (see above).

Plan to see a primary care doctor in the next two weeks.