Patient information: High-grade glioma in adults

HIGH-GRADE GLIOMA OVERVIEW

Primary brain tumors are cancers that originate in the brain. These tumors are very different from secondary brain tumors, which originally developed elsewhere in the body and spread (metastasized) to the brain.

Primary brain tumors develop from glial cells. Glial cells provide the structural backbone of the brain and support the function of the neurons (nerve cells), which are responsible for thought, sensation, muscle control, and coordination.

This article will discuss the symptoms, diagnosis, and treatment of high-grade (ie, malignant) gliomas, the largest subset of brain gliomas. Primary low-grade gliomas are discussed separately. (See "Patient information: Primary low-grade glioma in adults".)

CLASSIFICATION OF PRIMARY BRAIN TUMORS

Primary brain tumors are tumors that classified according to their appearance under the microscope. Gliomas are classified into four grades (I,II,III and IV), and the treatment and prognosis depend upon the tumor grade [1].

Grade I or II tumors are termed low-grade gliomas. The term malignant or high-grade glioma refers to tumors that are classified as:

• Grade III (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma)
• Grade IV (glioblastoma)

HIGH-GRADE GLIOMA SYMPTOMS

Gliomas cause symptoms by invading (growing) into and/or creating pressure in nearby normal brain tissue. The most common symptoms include:

• Headache

• Seizures — Seizures occur in more than one-half of patients with grade III gliomas, and about one-fourth of patients with grade IV gliomas. Seizures are caused by disorganized electrical activity in the brain. Medications can help to control seizures.

Other common symptoms of brain tumors include memory loss, muscle weakness, visual symptoms, difficulty in using or understanding language, and personality changes.

HIGH-GRADE GLIOMA TESTS

Imaging studies — If your healthcare provider is concerned about your symptoms, s/he may recommend a scan of the brain. This can be done using MRI or CT. Both tests provide a very detailed image of the brain. However, a CT or MRI cannot determine for sure if a mass is a cancerous tumor.

Biopsy — The only way to determine the type of tumor with certainty is for a neurosurgeon to remove a piece of the tumor (biopsy), usually during surgery. A pathologist will then examine the biopsy under a microscope.

However, a biopsy may be done without surgery; this approach is preferred if the tumor is located within a critical area of the brain or if you are too sick for surgery. In these circumstances, a procedure called a stereotactic needle biopsy is used to take a sample of the tumor by inserting a needle through the skull into the brain itself.

HIGH-GRADE GLIOMA INITIAL TREATMENT

Treatment of a high-grade glioma includes measures to relieve symptoms and eliminate or reduce the tumor. This may include surgery, radiation, and/or chemotherapy. (See "Adjuvant chemotherapy for malignant gliomas" and "Adjuvant radiation therapy for malignant gliomas" and "Clinical manifestations and initial surgical approach to patients with malignant gliomas".)

Everyone with high grade glioma is encouraged to participate in a clinical trial, if possible. (See 'Clinical trials' below.)

Symptom management — Seizures and swelling in the brain (cerebral edema) can cause serious symptoms that may be life-threatening. Although treatment of the tumor may eventually alleviate these symptoms, treatments aimed at controlling the symptoms may be required:

• Seizures — Anti-seizure medications can usually control seizures caused by a brain tumor.
• Cerebral edema — Cerebral edema is swelling in the brain. It is treated with glucocorticoids (also called steroids), most commonly dexamethasone (Decadron®).

To minimize side effects, the dose of dexamethasone is decreased gradually to the lowest level that controls symptoms.

• Hydrocephalus — Cerebrospinal fluid normally surrounds and cushions the brain. Hydrocephalus occurs when the flow of cerebrospinal fluid is blocked, which increases pressure within the brain. Treatment may require surgical to place a tube in the skull (called a shunt) to bypass the blockage and lower the pressure within the brain.

Surgery — The initial treatment of high-grade glioma usually involves removing as much of the tumor as possible with surgery. The amount of tumor that can be removed is determined by the tumor's size and location, and by how much normal brain will be damaged as a result of surgery. The standard approach is to remove as much of the tumor as possible, while sparing areas of the normal brain that control critical functions such as speech or balance.

Unfortunately, high-grade gliomas always have microscopic tumor cells that grow beyond the edge of the tumor. As a result, the tumor eventually regrows and few people with high-grade gliomas are cured with surgery alone. Radiation is typically recommended after surgery to kill any remaining tumor cells.

Surgery may not be possible if the tumor is located in a part of the brain that controls critical functions or if you are in poor health. In these circumstances, radiation may be recommended as an alternative to surgery (see 'Radiation' below.

Radiation — Even when the entire tumor appears to have been removed, almost all high-grade gliomas eventually come back. This is because tumor cells have grown into the surrounding normal brain. Radiation therapy uses high energy x-rays to kill cancer cells and is usually recommended following surgery to kill remaining tumor cells. This treatment is called adjuvant radiation. Radiation can help to delay a recurrence of the tumor, allowing you to live longer.

Radiation is generally given as a series of once daily treatments (called fractions) over several weeks. This approach helps to kill the greatest number of tumor cells and minimize side effects on normal brain cells. The area where the radiation is delivered (called the radiation field) is carefully calculated to include the smallest possible amount of normal brain as possible.

Most brain tumors that grow back are within 2 cm (one inch) of the original tumor location. As a result, radiation is usually delivered to the "involved field" (the original area of the tumor plus a small margin) rather than the whole brain.

Side effects — Radiation may kill normal brain cells as well as tumor cells, although tumor cells are somewhat more sensitive to the radiation. Damage to normal brain cells is often subtle, affecting mental sharpness and the ability to think and perform complex tasks (called cognitive impairment). Cognitive impairment tends to be more severe with larger radiation fields, tends to worsen over time, and is more of a problem in people who survive for several years after radiation treatments to the brain. It is not always possible to know if cognitive impairment is caused by radiation or a recurrence of the high-grade glioma.

Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment.

When used in combination with radiation therapy and surgery, chemotherapy may improve survival and quality of life in some patients with high-grade gliomas. The drug that are most widely used for high-grade glioma include temozolomide (Temodar®).

Temozolomide (Temodar®) is usually taken by mouth for five consecutive days every four weeks. It is usually taken during and after radiation therapy.

TREATMENT AFTER RECURRENCE

High-grade gliomas recur or regrow in most patients, usually within one to two years following diagnosis. There is controversy about the potential benefits of treatment when the tumor recurs [2]. If you decide to undergo treatment, you must consider the risks of treatment as well as the potential impact on your quality of life.

Treatment of a high-grade glioma that has recurred does not always improve survival compared to supportive care alone (ie, treatments to ease pain and other symptoms, (see 'End of life care' below.

You may benefit from retreatment if you have:

• Better overall health (termed the performance status, (table 1)

• A smaller amount of tumor present
• A lower-grade tumor (grade III rather than grade IV)
• A longer interval (eg, one year versus less than one year) between your original treatment and the recurrence

Options available for retreatment include surgery, various forms of radiation, and chemotherapy.

Surgery — It is not clear which people with recurrent high grade-glioma will benefit from surgery. The most important factor that predicts a longer survival after reoperation is a higher performance status (table 1). Other factors that increase the chances of prolonged survival include a younger age, a long interval between operations (eg, one year or more), and removing a larger amount of tissue with the second surgery.

The average survival of people who undergo surgery for recurrent grade IV gliomas ranges from 14 to 36 weeks. It is somewhat longer for patients with grade III tumors (56 to 88 weeks). Placing a Gliadel® wafer during surgery may prolong survival further. In one study, people who had a Gliadel® wafer placed had a significantly longer median survival (31 versus 23 weeks) compared to people who had a placebo wafer [3].

Radiation — Although there are exceptions, giving additional radiation is not usually possible in people with high-grade glioma recurrence because of the high risk of damage to normal brain tissue. Special techniques, such as stereotactic radiosurgery or brachytherapy, may permit additional radiation to be directly selectively to the tumor. However, there is no proof that these radiation treatments improve survival compared to supportive care alone.

Stereotactic radiosurgery involves the use of three-dimensional planning and specialized techniques to precisely deliver a dose of radiation to a small target in a single or limited number of treatments. The treatment does not involve surgery. By carefully focusing the radiation on the area containing the tumor, side effects to normal brain can be minimized. The initial radiosurgery system was called the gamma knife; however, other systems have been developed for this same purpose.

With interstitial brachytherapy, a radioactive substance (called "radioactive seeds") is placed directly into the area of tumor recurrence at the time of reoperation, where it slowly releases radiation that is active only over a very short distance. Although brachytherapy may be effective, it can cause serious side effects (see 'Side effects' above. At many institutions, the use of interstitial brachytherapy has decreased as experience with stereotactic radiosurgery has increased.

Chemotherapy — Chemotherapy is not particularly effective for recurrent high-grade gliomas. Enrollment in a clinical trial is recommended, when possible. If a clinical trial is not possible, treatment with bevacizumab may be an option.

Bevacizumab (Avastin®) — Bevacizumab (Avastin®) is an antibody (a type of protein) that targets a different protein called vascular endothelial growth factor (VEGF). VEGF causes a growing cancer to develop its own blood supply, which is essential for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.

Bevacizumab may be used alone or in combination with chemotherapy. However, bevacizumab can cause some serious side effects, including high blood pressure, bleeding, stroke, and infection.

OLIGODENDROGLIOMAS

Oligodendrogliomas represent an important subset of grade III gliomas, and account for about 10 percent of all primary gliomas [4]. These tumors have lost parts of chromosomes and have a very high likelihood of responding to chemotherapy, allowing the person a longer survival.

END OF LIFE CARE

In many people with high-grade glioma, the disease cannot be cured. Deciding when to stop treating the cancer can be difficult, and should involve the patient, family, friends, and the healthcare team.

Ending cancer treatment does not mean ending care for the patient. Hospice care is frequently recommended when a person is unlikely to live longer than six months. Hospice care involves treatment of all aspects of a patient and family's needs, including the physical (eg, pain relief), psychological, social, and spiritual aspects of suffering. This care may be given at home or in a nursing home or hospice facility, and usually involves multiple care providers, including a physician, registered nurse, nursing aide, a chaplain or religious leader, a social worker, and volunteers.

These providers work together to meet the patient and family's needs and significantly reduce their suffering. For more information about hospice, see www.hospicenet.org. (See "Hospice: Philosophy of care and appropriate utilization".)

CLINICAL TRIALS

Progress in treating high-grade gliomas requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

       www.cancer.gov/clinical_trials/learning/

       www.cancer.gov/clinical_trials/

       http://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Primary low-grade glioma in adults

Professional Level Information:
Anticoagulant and antiplatelet therapy in patients with brain tumors
Classification of brain tumors
Classification, diagnosis, and natural history of low-grade glioma
Clinical manifestations and initial surgical approach to patients with malignant gliomas
Clinical presentation and diagnosis of brain tumors
Diffuse pontine glioma
Ependymoma
Experimental treatment approaches for malignant gliomas
Focal brainstem glioma
Management of low-grade glioma
Management of seizures in patients with primary and metastatic brain tumors
Optic pathway glioma
Pathogenesis and biology of malignant gliomas
Adjuvant chemotherapy for malignant gliomas
Adjuvant radiation therapy for malignant gliomas
Hospice: Philosophy of care and appropriate utilization

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• National Cancer Institute

       1-800-4-CANCER
       (www.cancer.gov/cancertopics/pdq/treatment/adultbrain/Patient, available in Spanish)

• American Society of Clinical Oncology

      (www.cancer.net/portal/site/patient)

• National Comprehensive Cancer Network

      (www.nccn.com)

• American Cancer Society

       1-800-ACS-2345
      (www.cancer.org)

• American Brain Tumor Association

      (www.abta.org)

• National Brain Tumor Foundation

      (www.braintumor.org)

Patient Support — There are a number of online forums where patients can find information and support from other people with similar conditions.

• About.com Cancer Forum

      (http://cancer.about.com/forum)

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