Friday, October 12, 2007

Brain tumors Patient information: High-grade glioma in adults

INTRODUCTION — Primary malignant brain tumors are cancers that originate in the brain, mainly from glial cells. The different glial cell types in the normal brain include astrocytes, oligodendrocytes, and ependymal cells, and the tumors that arise from each of these are known as astrocytomas, oligodendrogliomas, and ependymomas, respectively. Some tumors may involve a mixture of astrocytes and oligodendrocytes and these are known as oligoastrocytomas.

Forty-two percent of primary brain tumors are gliomas and arise from these glial cells [1]. Proper identification of tumor type is important in choosing the best treatment. In contrast to primary brain tumors, secondary brain tumors (brain metastases) are cancers that have started elsewhere in the body and spread (metastasized) to the brain.

This topic review 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 classified according to their appearance under the microscope. Gliomas are the result of uncontrolled growth of normal glial cells. Glial cells provide the structural backbone of the brain and support the function of the neurons, which are directly responsible for thought, sensation, muscle control, and coordination. Thus, a tumor originating in glial cells can disrupt almost any function of the normal brain.

When gliomas are examined by the pathologist under the microscope, abnormalities can be seen that give an indication of whether the tumor is malignant or not. The World Health Organization (WHO) has established a system that classifies gliomas into four grades (I,II,III and IV) depending upon the microscopic appearance of the tumor [2]. This classification has proven critical since both the treatment and prognosis vary for different grade tumors.

The term malignant or high-grade glioma refers to tumors that are classified as either grade III (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, anaplastic ependymoma) or IV (glioblastoma), whereas grade I or II tumors are termed low-grade gliomas. High-grade gliomas have an appearance under the microscope that is very different from normal glial cells. Usually high-grade gliomas grow rapidly and have a poor prognosis (long-term outcome).

High-grade gliomas are subdivided based upon specific features of the individual cells. Anaplastic oligodendrogliomas, which arise from oligodendrocytes, are particularly noteworthy because they are usually more sensitive to chemotherapy and therefore are treated somewhat differently (see "Oligodendrogliomas" below). Anaplastic oligoastrocytomas have portions that are both astrocytic and oligodendroglial in appearance under the microscope. These usually have a better prognosis than anaplastic astrocytoma, but not as good as an anaplastic oligodendroglioma.

SYMPTOMS — Gliomas only rarely spread outside the brain, but instead produce symptoms by invading (growing) into and/or creating pressure upon nearby normal brain tissue.

The typical symptoms produced by high-grade gliomas were illustrated in a study of 788 newly-diagnosed patients [3]. Headache, which was present in more than one-half of patients, was the most common symptom. Seizures were the second most common symptom, occurring 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 and may produce many symptoms, including loss of consciousness and/or confusion. Most seizures caused by brain tumors stop on their own and only rarely result in permanent neurological problems. Medications are available which can lower the likelihood of further seizures.

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

DIAGNOSIS — Headaches, seizures, and all of the other symptoms described above can be caused by other neurologic illnesses like multiple sclerosis or brain infection. In addition, tumors other than high-grade gliomas (eg low-grade gliomas, brain metastases) can produce identical symptoms.

The physician will need to do a careful history and neurological examination as well as basic laboratory tests and imaging studies to define the cause of symptoms. Ultimately, the presence of a brain tumor is usually suggested by imaging studies such as a head computed tomography (CT or CAT scan) or magnetic resonance imaging (MRI). However, the specific tumor type can only be determined with certainty after a piece of the tumor is removed by a neurosurgeon and examined under the microscope by a pathologist.

Imaging studies — If a brain tumor is suspected, the physician will obtain a scan (or "picture") of the brain. This is done using either MRI or CT. MRI uses a magnet to image the brain, while CT uses x-rays. Both procedures give a very detailed image of the brain's structure, and both can show the presence of a "mass" and its location. However, a CT or MRI cannot definitively determine whether a mass is a tumor and cannot distinguish the specific type of tumor.

MRI usually provides more useful information when a brain tumor is suspected, and it is the preferred imaging study. However, CT scans may be more readily available than MRI, so a brain CT is often the first test that is ordered. MRI is not possible in patients with pacemakers, metal fragments or other medical devices and CT is usually done under those circumstances.

Positron-emission tomography (PET) scanning is an additional imaging test that may be done in patients during treatment for a brain tumor. It can help distinguish "active or growing" tumor from "inactive" tumor. During a PET scan, glucose (a sugar) with a radioactive tag is injected into the bloodstream and circulates to the brain. Tumor cells tend to accumulate a higher concentration of glucose, and can thus be differentiated from normal areas of brain. PET scanning may be important after patients have been treated with radiation, as this type of treatment often causes changes on the CT or MRI that can mimic growth of a tumor.

Biopsy — Accurate classification of a tumor requires that a pathologist examine a piece of the tumor under a microscope. A biopsy is usually obtained in conjunction with surgery when a high-grade glioma is suspected (see "Surgery" belowsee "Surgery" below).

However, only a biopsy may be done if the tumor is located within a critical area of the brain that cannot be safely approached by surgery, or if the patient is too sick for surgery. In these circumstances, using a procedure called a stereotactic needle biopsy, the tumor can be safely sampled by inserting a needle through the skull into the brain itself, using CT or MRI to accurately position the biopsy needle.

INITIAL TREATMENT — Optimal care of the patient with a high-grade glioma includes measures to alleviate symptoms as well as specific treatments aimed at the tumor, including surgery, radiation, and chemotherapy. The specific treatment plan is determined by the type of tumor, whether the tumor is malignant or not and the location of the tumor in the brain.

Symptom management — Seizures, cerebral edema (swelling in the brain around the tumor), and hydrocephalus (increased pressure within the brain due to blockage of the flow of the cerebrospinal fluid, which normally surrounds and cushions the brain) can cause serious symptoms that may be life-threatening. Although treatment of the tumor may eventually alleviate these symptoms, more specific measures aimed at controlling the symptoms may be required: Seizures — Anticonvulsants are usually successful in controlling seizures associated with brain tumors. Cerebral edema — Swelling of the brain is treated with steroids, and the most commonly used steroid is dexamethasone (Decadron®). Although the need for dexamethasone may be temporary if treatment of the tumor results in decreased edema, corticosteroid use may be prolonged if a tumor cannot be removed surgically, or if it regrows and there is no other way to control the swelling.

Prolonged use of steroids is generally avoided if possible. Long-term use can be associated with side effects, including weight gain, stomach ulcers, gastrointestinal bleeding, personality changes, thinning of the skin, loss of bone strength, cataracts, sleep problems, hyperactivity and diabetes. Thus, in order to minimize complications, the dose of dexamethasone is decreased gradually to the lowest level that controls symptoms. Hydrocephalus — Hydrocephalus may require surgery with insertion of internal tubing to bypass the blockage and lower the pressure within the brain.

Surgery — The surgical removal (resection) of as much of the tumor as possible is usually the initial treatment. Unfortunately, high-grade gliomas always have microscopic tumor cells that grow beyond the edge of the tumor. These cells cannot be seen by the surgeon and therefore, cannot be removed. As a result, eventual tumor regrowth is common and few, if any, patients with high-grade gliomas are cured with surgery alone. Surgery may not be possible if the tumor is located in a part of the brain controlling critical functions or if the patient is in poor overall medical condition. In these circumstances a biopsy is usually done and radiation may be recommended as an alternative to surgery (see "Radiation" belowsee "Radiation" below).

The extent to which a high-grade glioma can be resected is determined by its size and location, and by how much damage will result to normal brain as a consequence of the 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. Radiation is typically recommended after surgery to kill any tumor cells that may be left behind.

Radiation — Even when the entire tumor appears to have been removed by the surgeon, almost all high-grade gliomas eventually come back. This is because individual glioma tumor cells have grown into the surrounding normal brain cannot be removed by the surgeon. Radiation (also sometimes referred to as radiotherapy or x-ray therapy) uses exposure to high energy x-rays to kill cancer cells and is usually recommended following surgery to kill these residual tumor cells. The use of radiation in this manner is referred to as "adjuvant" radiation, and its benefits may include a delay in recurrence of the tumor and a longer survival.

Radiation is generally given as a series of daily treatments (called fractions) over several weeks. This "fractionated" approach to administering radiation is important to maximize the killing of tumor cells and minimize side effects on normal adjacent brain. The area over which the radiation is administered (called the radiation field) is carefully calculated to avoid including as much normal brain as is feasible.

The finding that most brain tumors grow back are within 2 cm (one inch) of the original tumor location provided the rationale for treating the "involved field" (the original area of the tumor plus a small margin of the adjacent brain) rather than the whole brain with radiation. Whole brain and involved field radiation may be equally effective at delaying recurrence of high-grade gliomas, but involved field radiation results in fewer side effects because less of the normal brain is included in the radiation field. As a result, involved field radiation has become the standard approach to adjuvant radiation for high-grade gliomas.

Side effects — Radiation kills normal brain cells as well as tumor cells, even though tumor cells are somewhat more sensitive to the radiation. In fact, there is evidence that radiation impairs the ability of the brain to generate new brain cells and this may account for some of the side effects of radiation Thus, as with surgery, radiation must be used in a way to balance the benefits versus the side effects of treatment.

Radiation necrosis (the death of large numbers of normal brain cells) is a serious side effect and may occur many months or years after radiation is completed. This can be associated with a severe loss of brain function and is generally not a reversible condition. Fortunately, radiation necrosis is uncommon with the doses of radiation that are currently used.

More commonly, radiation damages the surrounding normal brain cells in a more subtle way, resulting in gradually decreasing mental sharpness and 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 patients who survive for several years after undergoing radiation to the brain. It is not always possible to know whether cognitive impairment is the result of the radiation or whether it might be due to recurrence of the high-grade glioma.

Chemotherapy — Chemotherapy when administered in addition to surgery and radiation may improve survival and quality of life in some patients with high-grade gliomas. 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 give rise to side effects during treatment.

The use of chemotherapy in addition to surgery and radiation in patients with high-grade glioma has been studied extensively. The drugs that are most widely used today are carmustine (BCNU), temozolomide (Temodar), and a three-drug combination of procarbazine, CCNU and vincristine, abbreviated "PCV". Overall, the addition of adjuvant chemotherapy consistently increases the proportion of patients who become long-term survivors from less than 5 percent to approximately 15 to 20 percent [5].

Carmustine — Carmustine, which is usually given by vein, was the first chemotherapy drug that was shown to improve survival in patients with high-grade glioma. In an early trial, all patients received surgery, and either radiation alone, carmustine alone, or a combination of carmustine plus radiation [4]. Compared to patients receiving radiation alone, those treated with carmustine and radiation were significantly more likely to be alive at 18 months (19 versus 4 percent).

Gliadel — A new form of carmustine has been developed in which the drug is embedded in wafers (called Gliadel® wafers). The Gliadel wafer is implanted at the time of surgery into the area from which tumor has been removed. The wafer then slowly releases the carmustine into the area around the tumor. By giving the drug in this way, the concentration of carmustine is much higher locally, while the rest of the body is spared most of the toxic side effects.

The effectiveness of Gliadel wafers was assessed in a trial of 240 patients with high-grade gliomas, all of whom received standard radiation following surgery; one-half of the patients had a Gliadel wafer implanted after surgery while the others did not [6]. Use of Gliadel was associated with a two month prolongation in average survival, a result quite similar to that achieved with the intravenous form of the drug.

Temozolomide — Temozolomide is the newest chemotherapy drug approved for the treatment of high-grade gliomas, and clinical studies indicate that it has a similar level of activity as carmustine and procarbazine. Temozolomide is usually given by mouth for five consecutive days every four weeks. One difference compared to most other chemotherapy drugs is that temozolomide is usually given both during the course of radiation as well as afterwards.

The benefit of using temozolomide and radiation compared with radiation alone was demonstrated in a trial of 573 patients who underwent surgery for a glioblastoma [7]. The benefits of temozolomide included prolongation in average survival, and a higher likelihood of being alive at two years (26 versus 10 percent). Although these results are similar to those that can be achieved with adjuvant carmustine, temozolomide is associated with fewer side effects, and the ease of oral administration makes it a more readily tolerated therapy.

Combination chemotherapy — The combination of procarbazine, CCNU, and vincristine (termed the PCV regimen) is also used as an adjuvant chemotherapy regimen. However, there is no evidence that PCV is better than single agent carmustine or temozolomide. Side effects may be more frequent and severe with PCV compared to the other typically used drugs.

Summary — The initial treatment for a patient with a high-grade glioma is surgery, with the goal of removing as much tumor as possible. Surgery can often alleviate symptoms and improve neurological function, and might prolong survival, although this is controversial. Since virtually no patients with high-grade glioma are cured by surgery alone, adjuvant radiation and chemotherapy are typically recommended, even in patients whose tumor appears to have been completely removed ("gross total resection"). Clinical studies have demonstrated that adjuvant radiation is the most important factor in improving survival, but adjuvant chemotherapy increases the fraction of patients surviving long-term.

The most widely used drugs for adjuvant chemotherapy are temozolomide, carmustine, or the combination PCV regimen. Alternatively, a new formulation of carmustine, Gliadel wafers, may be embedded at the time of surgery into the site from which the tumor was removed with similar results. The optimal regimen and duration of adjuvant chemotherapy are unclear.

TREATMENT AFTER RECURRENCE — Despite the progress achieved with adjuvant treatments, high-grade gliomas recur or regrow in most patients, usually within one to two years following diagnosis. The potential benefits of treatment for a recurrent brain tumor are controversial [8] and the use of any therapy must consider the risks associated with treatment and the impact on quality of life.

There are no trials that definitively show that retreatment at the time of recurrence improves outcomes compared to supportive care alone (ie, no specific antitumor treatment). Although some reviews suggest that treatment of recurrent brain tumor improves the likelihood of being alive at one year [8], the interpretation of these results is difficult because patients who were doing poorly tended not to receive further treatment.

The factors that are associated with an improved chance of benefit from retreatment include the following: Better overall health and "functional" status (termed the performance status, show 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 the original treatment and the recurrence

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

Surgery — The indications for reoperation in patients with recurrent high grade glioma after initial treatment are not well-established. The most important factor that predicts a longer survival after reoperation is a higher functional or performance status (show table 1). Other favorable prognostic variables include younger age, a long interval between operations (eg, one year or more), and greater extent of the second surgical resection.

The average survival for patients undergoing 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).

Radiation — Although there are exceptions, re-irradiation with conventional radiation is usually not possible in patients with tumor recurrence because of the high risk of damage to the normal brain. However, special techniques, such as stereotactic radiosurgery or brachytherapy, may permit additional radiation to be given selectively to the tumor.

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. 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 such as radiation necrosis (see "Side effects" above). At many institutions, the use of interstitial brachytherapy has decreased as experience with stereotactic radiosurgery has increased.

Chemotherapy — Overall, traditional forms of chemotherapy for recurrent malignant gliomas have not been particularly effective. The same agents (carmustine, procarbazine, and temozolomide) used when the patient was first diagnosed have also been used in patients with recurrent high-grade glioma. Other drugs that have been used include carboplatin, thalidomide, irinotecan, and etoposide. In general, if the patient had received adjuvant chemotherapy when first treated, a different agent will be chosen to treat a recurrence. None of these single agents has been shown to be superior to the others.

Summary — For patients with tumor recurrence, reoperation may be indicated in carefully selected cases (eg, young patients with a good functional level and a long interval since the original surgery), although these criteria are not firmly established. Fractionated stereotactic radiotherapy may provide an alternative approach without the side effects of chemotherapy.

OLIGODENDROGLIOMAS — Anaplastic oligodendrogliomas represent an important subset of grade III gliomas, and may account for 19 percent of all primary gliomas [1]. These tumors are more chemotherapy-responsive than other high-grade gliomas. Tests have shown that tumors that have lost parts of chromosomes 1 and 19 have a very high likelihood of responding to chemotherapy and having prolonged survival.

Although a preliminary report of a trial examining the benefit of the PCV chemotherapy regimen in patients undergoing surgery and radiation therapy for anaplastic oligodendrogliomas did not show any benefit from this approach, this study was conducted prior to the development of testing for these specific chromosome abnormalities [9].

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:

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 patients 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 ( Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

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

People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
National Comprehensive Cancer Network

American Cancer Society

National Library of Medicine

American Brain Tumor Association

National Brain Tumor Foundation

National Institute of Neurological Disorders and Stroke


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