Primary low-grade glioma in adults

INTRODUCTION — Malignant brain tumors are cancers that originate either in the brain itself (primary brain tumors) or spread (metastasize) to the brain from a cancer elsewhere in the body (also known as secondary (malignant) brain tumors or brain metastases). Secondary brain tumors are much more common, and their treatment is determined by where the cancer began and by the areas where the cancer has spread elsewhere in the body.

In this topic review, we will discuss the symptoms, diagnosis and treatment of low-grade gliomas, an important category of primary brain tumors.

CLASSIFICATION OF PRIMARY BRAIN TUMORS — Primary brain tumors are classified according to their appearance under the microscope, and what type of brain cell they are thought to have arisen from. Over 80 percent of all malignancies that arise in the brain fall into the general category called a "glioma" [1].

Gliomas (also sometimes called astrocytomas) are the result of uncontrolled growth of glial cells (also called astrocytes). 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.

Low-grade versus high-grade gliomas — Examination of gliomas through a microscope shows changes of the glial cells that give information about the aggressiveness of the cancer (ie, the relative degree of malignancy). This tends to correlate with the speed with which the tumor is growing and damaging normal brain cells. Based on this, the World Health Organization (WHO) classifies gliomas into four grades depending on prognosis [2].

The term low-grade glioma refers to those tumors in Grades I and II of this classification. They have fewer aggressive characteristics and therefore are more likely to grow slowly, as opposed to high-grade gliomas, which show more aggressive features of malignancy and are more likely to grow rapidly. This distinction of a glioma as either low-grade or high-grade is an important one, since both the prognosis and the approaches to treatment are different [1]. This topic review will focus on low-grade gliomas. For information about high-grade gliomas, see "Patient information: High-grade glioma in adults".

Types of low-grade glioma — Low-grade gliomas are subdivided into different types based upon the microscopic appearance of the tumor. The more common subtypes are:

Diffuse astrocytomas — Diffuse astrocytomas are the most common low-grade glioma. They are usually diagnosed in individuals in their late thirties. The average survival is approximately seven years, although about 20 percent of patients survive ten years or more.

Juvenile pilocytic astrocytomas — These tumors occur almost exclusively in patients less than 25 years of age. It is important to distinguish juvenile pilocytic astrocytomas from other low-grade gliomas because these tumors tend to progress very slowly. Unlike diffuse astrocytomas, over 80 percent of patients survive ten years or more, generally with a very good functional level.

Oligodendrogliomas — Oligodendrogliomas can be slow-growing tumors. The prognosis of patients with this tumor type depends in part upon the presence or absence of a portion of human Chromosome 1 (1p). Patients with loss of this chromosome tend to survive longer and are more responsive to chemotherapy. Patients who have tumors that have components of both astrocytomas and oligodendrogliomas (tumors called "oligoastrocytomas"), tend to have tumors that behave like diffuse astrocytomas.

Gangliogliomas — These tumors have features of both gliomas and of tumors arising from neurons, the other main type of cell within the brain besides glial cells. These tumors tend to grow very slowly, and many patients do well for a long time.

Mixed gliomas — Some low-grade gliomas consist of mixtures of different tumor subtypes (eg, diffuse astrocytoma and oligodendroglioma). These tend to behave similarly to diffuse astrocytomas.

SYMPTOMS — Low-grade gliomas do not spread outside the brain, but instead grow into the normal brain tissue, creating symptoms as the tumor grows locally. This can disrupt connections between normal brain cells, and can also create pressure on the adjacent brain. The brain cannot expand when there is a tumor growing within it since it is confined within the skull. As a result, even a relatively small, slow-growing tumor can cause severe brain dysfunction and death, particularly if the tumor is in a critical area of the brain.

In many patients, a seizure is the first symptom of a low-grade glioma. Seizures, which can also occur in other conditions such as epilepsy, are caused by disorganized electrical activity in the brain. They can cause loss of consciousness, involuntary movements, and/or loss of muscle control throughout the body.

Seizures can often be completely controlled with medications. In patients with a low-grade glioma who are first diagnosed after a seizure, no neurologic signs or symptoms may be evident once the seizure is controlled with medication.

Other patients have symptoms due to swelling around the tumor (called cerebral edema) or blockage of the normal cerebrospinal fluid that circulates within the brain (called obstructive hydrocephalus). In either case, symptoms can include headache, nausea and vomiting, diminished consciousness, weakness or numbness, and loss of mental sharpness or difficulty concentrating. The area of the brain affected by the tumor and/or the swelling will determine the specific symptoms.

DIAGNOSIS — All of the symptoms described above, including seizures, can be caused by neurologic illnesses other than tumors, and by non-neurologic diseases. A clinician will need to do a careful history and physical examination as well as basic laboratory and x-ray tests to define the cause of symptoms or seizures. The presence of a brain tumor is often established by x-ray or imaging studies.

Imaging studies — If a brain tumor is suspected, the physician will want to obtain a x-ray scan of the brain. This is done using either magnetic resonance imaging (also known as an MRI) or computed tomography (also known as CT or CAT scan). A major difference between an MRI and a CT scan is that the MRI uses a magnet to image the brain, while CT uses x-rays. Both give a detailed image of the brain's structure, and both can show the presence of a tumor and its location.

CT scans are generally more available and less expensive than MRI scans, so often a brain CT is the first test that is ordered when a neurologic condition affecting the brain is being evaluated. However, the MRI provides much more useful information when a brain tumor is suspected. Thus, it is the preferred test in most situations. However, there are a few situations where a CT scan can offer advantages. Although not every tumor can be visualized by MRI or CT, most can be identified.

Sometimes, the findings on the brain CT or MRI are sufficiently characteristic that the diagnosis of a low-grade glioma may be fairly certain. In such cases, a biopsy may not be necessary. However, in most cases, a biopsy is recommended to establish the type of tumor that is present since it may impact on treatment (See "Treatment" below).

It is important to characterize a brain tumor as a low-grade glioma, high-grade glioma, or a different type of tumor altogether. An additional noninvasive x-ray test that may help in this distinction is a positron-emission tomography, PET scan. During this test, glucose (a sugar) with a radioactive tag is injected into the bloodstream, which then circulates to the brain. Differences in the metabolism of glucose between normal cells and various types of cancer cells permit identification of a tumor, and may permit the distinction between low-grade gliomas, high-grade gliomas, and other brain tumors.

Biopsy — A biopsy is usually required to establish the definitive diagnosis and subtype of a brain tumor and plan appropriate treatment. Biopsy involves the removal of at least a small amount of tissue from the brain for microscopic examination.

A brain biopsy may be done in conjunction with surgery to remove the tumor. Alternatively, a small sample may be removed from the tumor by stereotactic needle biopsy, which involves the insertion of a needle through the skull into the precise area of the tumor under x-ray (radiographic) guidance. Although both surgical biopsy and stereotactic needle biopsy are usually safe, neurologic damage is a potential complication.

If the findings on CT, MRI, and PET are characteristic, biopsy of the tumor may be deferred until symptoms worsen or there is evidence of tumor growth or a change in the imaging characteristics that suggest that the tumor is becoming more aggressive. The decision regarding the optimal timing of a biopsy requires the physician and patient to carefully weigh the risks of the biopsy against the benefit of knowing the specific type of tumor that is present.

TREATMENT — Treatment of a low-grade glioma has to take into account both the management of symptoms as well as specific approaches to remove the tumor or reduce its size. The optimal treatment of low grade-glioma (particularly the timing of treatment) is a controversial area, and treatment decisions must balance the benefits of therapy against the potential for treatment-related complications.

Symptom management — Seizures, cerebral edema (swelling in the brain around the tumor), and obstructive hydrocephalus (increased pressure within the brain due to blockage of the flow of cerebrospinal fluid within the brain) can all result in serious symptoms for patients with brain tumors. Each of these requires a different therapeutic approach: The same medications used to treat epilepsy are usually successful in controlling seizures associated with brain tumors, such as low-grade gliomas. However, seizures may be more difficult to control in patients with brain tumors, particularly low-grade gliomas. If medications are not effective, surgery to remove part of the tumor may be recommended in an attempt to reduce seizure activity. Cerebral edema usually can be treated successfully with a class of drugs called corticosteroids (steroids); the most commonly used steroid is dexamethasone (Decadron). Dexamethasone use can be temporary if specific treatment of the tumor is planned, and is expected to decrease edema. Dexamethasone may be used for a more prolonged period of time if treatment is deferred, and may be particularly useful in the late phases of the illness, such as if the tumor recurs and there is no other way to control cerebral edema.

One of the problems with long-term use of dexamethasone (particularly high doses) is the potential for side effects (eg, ulcers, bleeding from the gastrointestinal tract, behavioral changes, thinning of the skin, loss of bone strength, high blood sugar). Thus, the dose of dexamethasone is tapered to achieve the lowest dose that can effectively control symptoms, yet minimize long-term complications. Obstructive hydrocephalus may require surgery to bypass the blockage and lower the pressure within the brain.

Antitumor therapy — Surgery, radiation therapy, and chemotherapy may be used to treat a low-grade glioma, either separately or in combination.

Surgery — The objective of surgery is to remove (resect) as much of the tumor as possible, while minimizing damage to the normal brain. While patients with juvenile pilocytic astrocytomas do particularly well after removal of their tumors, the impact of surgery on the survival of patients with other types of low-grade glioma is less clear [4].

Low-grade gliomas infiltrate into normal brain, and there is often no distinct boundary between the tumor and normal brain. As a result, efforts to remove all tumor cells inevitably removes some of the normal brain and can leave behind tumor cells. The remaining glioma cells continue to grow, eventually causing additional damage to the remaining normal brain, and recurrence of symptoms. Thus, surgery, even when extensive, rarely results in cure of a adults with an infiltrative low-grade glioma.

Whether or not all patients should have surgery after initial diagnosis is an area of controversy [4-7]: Some physicians recommend that resection of as much tumor as possible be attempted in all patients as soon as the diagnosis of a brain tumor is made. This recommendation is based upon studies suggesting that patients who have immediate surgery survive longer, possibly because the tumor is less likely to change into a more aggressive form. Other physicians recommend that carefully selected patients initially be observed without therapy, until there is evidence of tumor growth or an increase in symptoms despite medical therapy. The rationale behind this approach is that low-grade gliomas may progress very slowly, surgery can create more symptoms than are caused by the tumor, and surgery undertaken later may be equally effective [6].

The physician and patient must try to balance the benefits of removing tumor versus the neurologic symptoms that can be expected from damage to normal brain. The extent of surgery and whether it is feasible are influenced heavily by the location of the tumor within the brain: If the tumor is in an area of the brain controlling one or more critical functions, surgery may result in severe damage. In this setting, the physician may recommend against surgery or recommend limiting the amount of tumor removed. If the tumor is in a less critical area of the brain, the physician may recommend trying to remove as much of the tumor as possible.

Other accepted indications for neurosurgery include increased pressure within the brain, a neurological deficit due to the tumor or a bleed (hemorrhage) into the tumor, or seizures that are unresponsive to medical therapy [4].

Radiation therapy — Radiation therapy (also called radiotherapy or x-ray therapy) uses high energy x-rays that are carefully aimed at the area of the brain affected by the tumor. Radiation therapy is generally given in a series of treatments over several weeks. The total radiation dose, which is based upon the number of treatments and the amount of radiation administered per treatment, is carefully calculated to maximize the killing of tumor cells and minimize damage to the normal brain.

Radiation therapy may be recommended in three circumstances in patients with low-grade gliomas: Radiation can be given after surgery, with the objective of eradicating tumor cells that were not removed at the time of surgery. The effectiveness of immediate radiation therapy after surgery is unclear. Because benefit is uncertain [8], and radiation has the potential for long-term neurologic side effects, postoperative radiation is often not recommended (see below). Radiation therapy may be the preferred treatment when a symptomatic low-grade glioma has been diagnosed in a critical area of the brain that cannot be surgically removed, and therapy is felt to be necessary. Radiotherapy can be utilized later in the course of the illness, when there is evidence that the tumor has recurred and is causing symptoms. Use of radiation therapy at this time may be dependent upon how much radiation was given earlier, since radiation therapy can usually not be administered in full doses to the same area of the brain more than once.

A major problem with radiation therapy is treatment-related side effects. Radiation kills both tumor cells and normal cells, although tumor cells are somewhat more sensitive to the effects of radiation. Nevertheless, radiation therapy cannot kill all tumor cells without damaging adjacent normal brain, and this results in treatment-related side effects.

The most serious side effect is radiation necrosis (the death of large numbers of normal brain cells), which may occur many months after the radiation therapy is given, particularly if high doses are used [9]. This is generally not a reversible condition, and may require surgery to remove the area of dead tissue. Fortunately, this complication is uncommon with conventional radiation doses.

More commonly, radiation may damage the surrounding normal brain cells in a more subtle way, resulting in gradually worsening impairment of mental sharpness and ability to think and concentrate (called impaired cognition) [10-12]. This cognitive impairment, which tends to be greater 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 therapy to the brain. It is difficult to know for certain whether impaired cognition results from the radiation or whether it might be due to the disease itself. Nevertheless, although the risk of worsened cognition after radiation is still studied, this possibility remains one of the main reasons why radiation therapy is often deferred until it is absolutely necessary.

Chemotherapy — Regardless of the initial form of therapy, low-grade gliomas generally progress over time; the time frame may be long, sometimes as long as ten years or more after the original diagnosis. They may also develop an aggressive (more malignant) phase after a variable period of time. This aggressive phase is characterized by more rapid tumor growth and progressive neurologic dysfunction.

Therapeutic options are limited in the late phases of the disease, since surgery and radiation therapy are unlikely to be useful or feasible. In such cases, chemotherapy may be considered.

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 or reproduce themselves. 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 the blood cells are produced), the hair roots (follicles), and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment. In general, side effects are more frequent when two or more drugs are administered simultaneously (termed combination chemotherapy, see below), and with higher as compared to lower doses of chemotherapy. Most chemotherapy drugs that are used for the treatment of brain tumors are administered into the vein, although some (temozolomide, for example) are effective when given by mouth.

Chemotherapy is not curative, but it produces short-term benefits (months rather than years) in some patients. Tumor shrinkage (which may be accompanied by an improvement in symptoms) has been seen in selected patients using various drugs or combinations, such as temozolomide (Temodar) or the "PCV" combination (procarbazine, lomustine, and vincristine). Patients with the oligodendroglioma subtype (especially those with the chromosome1p deletion) are most likely to benefit from chemotherapy [13]; response rates in other types of low-grade gliomas have generally been disappointing.

The use of chemotherapy in conjunction with radiation therapy earlier in the course of low-grade glioma has not been adequately studied. Thus, benefit from this approach has not been established, and it should only be used in the setting of a clinical research study.

SUMMARY — Low-grade gliomas are cancers arising in the brain that tend to be slow-growing, and associated with a long natural history. Although patients with these tumors are only rarely cured, most are able to maintain a high level of functioning for a number of years. Careful medical management of seizures, brain swelling, and other complications, combined with the timely use of surgery, radiation therapy, and perhaps chemotherapy, can help preserve a high quality of life and minimize disability.

CLINICAL TRIALS — Progress in treating low-grade glioma requires that better treatments be identified through clinical trials, which are conducted all over the world. Many clinical trials are ongoing. Patients may be eligible for one of these clinical trials, many of which are sponsored by the National Cancer Institute (see below). Patients should ask doctor about participating in a study.

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 (www.patients.uptodate.com). 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

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Brain Tumor Association

(www.abta.org)
National Brain Tumor Foundation

(www.braintumor.org)
National Institute of Neurological Disorders and Stroke

(www.ninds.nih.gov)


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