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Glioblastoma

 Glioblastoma is the most challenging form of brain tumor.  At the UCSD Brain Tumor Center, we have assembled specialists who focus specifically on this type of tumor.  Survival is improving and advanced clinical trials are available for patients who are treated at Moores Cancer Center.

Glioblastoma multiforme and anaplastic gliomas: 

A PATIENT AND CAREGIVER GUIDE

First clues that something is wrong....

Brain tumors are diagnosed in many different ways, often because the patient is experiencing symptoms.  Because brain tumors can occur in any part of the brain....the symptoms they cause can literally affect any of our functions.  A person may notice a problem with balance or strength or numbness, they may experience a headache or have a seizure, they may notice a blind spot while reading, sometimes a family member will notice confusion or the patient may feel their memory is affected.   Ultimately, a doctor is seen and an MRI scan or CT scan is ordered and this shows the problem.  

Learning more about the tumor through the biopsy  or examination of the brain tumor tissue....

Once a brain tumor is detected on a CT or MRI scan, a neurosurgeon will usually need to obtain a portion of tumor tissue for examination by a neuropathologist.  This can be done a procedure where diagnosis is the only goal (a biopsy) or it can also be done as part of a surgery to remove the tumor (a resection).  In either case, the neuropathologist will analyze the tumor tissue give it a type and grade.  Because the 'type' and 'grade' of a tumor is very much tied to prognosis and treatment strategies, this is a very important piece of information that is needed for each brain tumor.   

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 or 'histologic type', for example, astrocytoma or gangliogloma or oligodendroglioma or neurocytoma.....etc, etc.  

-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, (histologic type and grade) are then combined, as in "grade 4 astrocytoma". Once a tumor has been given a name and a grade, brain tumor specialists can provide you advice about treatment choices, prognosis, and provide useful health-care information to brain tumor patients and their families.

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

Examples:  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?

Examples:  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:

Astrocytomas and oligodendrogliomas are very common primary tumors of the adult brain. Both tumors are called gliomas, which is a more general term referring to tumors that arise from cells of the brain itself rather than traveling, or metastasizing, to the brain from another location in the body.  This group of tumors (gliomas) can be slow growing, in which case they are referred to as low-grade or grades 1 and 2, or rapidly growing (also called high-grade or anaplastic or muliforme or grades 3 and 4). This page will provide some important information about the diagnosis and treatment of high-grade gliomas.

High-grade gliomas are diagnosed by a direct examination of the a specimen of tumor by a pathologist.  This is referred to as a biopsy analysis. 

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.  UCSD 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 (619-543-5540) 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

For most patients who are working at the time their illness strikes, a 3 - 6 month period of disability is a good idea. It is usually difficult to have daily radiation treatments while working, for example, and the stress and fatigue produced by the illness and therapy require plenty of rest. Because tumors in brain tissue often directly effect mental ability or physical ability, many types of work become simply too challenging or even impossible. For patients who are significantly affected by their tumor, permanent disability is often best. The patient and close family members are usually best able to determine what work will be practical.

Inpatient admission to the UCSD Thornton or Hillcrest Hospitals

Following surgery, if it becomes necessary to be admitted to UCSD for treatment or for a complication, patients are usually admitted to the 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 UCSD 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 UCSD 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.  

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.

Education at home

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

UCSD Brain Tumor Center at 619-543-5540

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

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

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Additional Information on Brain Tumors In General

Types of Primary Brain Tumors

There are many types of primary brain tumors. Primary brain tumors are named according to the type of cells or the part of the brain in which they begin. For example, most primary brain tumors begin in glial cells. This type of tumor is called a glioma.

Among adults, the most common types are:

  • Astrocytoma: The tumor arises from star-shaped glial cells called astrocytes. It can be any grade. In adults, an astrocytoma most often arises in the cerebrum.
    • Grade I or II astrocytoma: It may be called a low-grade glioma.
    • Grade III astrocytoma: It's sometimes called a high-grade or an anaplastic astrocytoma.
    • Grade IV astrocytoma: It may be called a glioblastoma or malignant astrocytic glioma.
  • Meningioma: The tumor arises in the meninges. It can be grade I, II, or III. It's usually benign (grade I) and grows slowly.

  • Oligodendroglioma: The tumor arises from cells that make the fatty substance that covers and protects nerves. It usually occurs in the cerebrum. It's most common in middle-aged adults. It can be grade II or III.

    Among children, the most common types are:

  • Medulloblastoma: The tumor usually arises in the cerebellum. It's sometimes called a primitive neuroectodermal tumor. It is grade IV.

  • Grade I or II astrocytoma: In children, this lowgrade tumor occurs anywhere in the brain. The most common astrocytoma among children is juvenile pilocytic astrocytoma. It's grade I.

  • Ependymoma: The tumor arises from cells that line the ventricles or the central canal of the spinal cord. It's most commonly found in children and young adults. It can be grade I, II, or III.

  • Brain stem glioma: The tumor occurs in the lowest part of the brain. It can be a low-grade or high-grade tumor. The most common type is diffuse intrinsic pontine glioma .