INTRODUCTION — Meningiomas are brain tumors that develop in the tissue that surrounds and protects the outer surface of the brain and spinal cord (the meninges). Meningiomas account for about 15 to 30 percent of all tumors that originate in the brain. They are seen most frequently after age 40, and are more common in women than men [1].
Meningiomas can occur in any part of the lining over the brain or spinal cord (show figure 1). About 90 percent occur within the head: around the cerebral hemispheres (just inside the skull), on the under surface of the brain (at the base of the skull), or in the lower part of the brain (the brainstem, which is located just above the spinal cord). Most of the remaining meningiomas arise in the optic nerve sheath (which protects the nerve connecting the eye to the brain) and around the spinal cord.
CLASSIFICATION OF MENINGIOMA — Meningiomas are classified according to their appearance when examined under the microscope and their position in the brain. Microscopic examination provides information about the cells comprising the meningioma, including how rapidly the cells are dividing (referred to as the "mitotic index") and whether the meningioma cells are growing into or invading the adjacent normal brain. Classification provides valuable information about the likelihood of meningioma returning ("recurring") after treatment.
The most widely used classification system is that of the World Health Organization (WHO), which separates meningiomas into three categories:
Grade I or benign meningiomas — Benign meningiomas are slow-growing tumors that have well-defined borders and do not appear to invade the adjacent normal brain. Few meningioma cells are actively dividing (ie, the tumor has a low mitotic index). Approximately 90 percent of all meningiomas fall into this category.
Grade II or atypical meningiomas — Atypical meningiomas contain more cells that are actively dividing (ie, they have a higher mitotic index) than benign meningiomas. In addition, grade II tumors have other features that suggest that they are growing more rapidly than benign meningiomas. These lesions are more likely to recur than benign tumors. Atypical meningiomas constitute about 5 to 7 percent of all meningiomas.
Grade III or malignant meningiomas — Malignant meningiomas, which are sometimes referred to as anaplastic meningiomas, have the highest mitotic index. Malignant meningiomas are likely to recur after treatment. These comprise 1 to 3 percent of all meningiomas.
A higher grade correlates with a worse prognosis. Patients with benign (grade I) meningiomas generally do well, with 80 percent or more remaining free of progression or recurrence after their initial treatment. In contrast, patients with atypical (grade II) and malignant (grade III) meningiomas are at much higher risk for recurrence. In one report, patients with atypical meningiomas had recurrence within an average of five years, while patients with malignant meningiomas had recurrence within an average of only two years [2].
RISK FACTORS — The cause of meningiomas is not well understood, but may include both genetic (inherited) and environmental factors. Several conditions have been associated with an increased risk for the development of a meningioma [1]: Neurofibromatosis - Neurofibromatosis type 2 is a rare inherited disease that usually appears first during childhood. This disorder affects the skin and the nervous system, and increases the risk of meningiomas as well as other brain tumors. Affected patients may develop multiple meningiomas. Previous radiation therapy treatment - Patients who have had radiation exposure to the head have an increased risk for developing a meningioma, especially 10 to 20 years after treatment. Individuals who underwent irradiation of the brain and spinal cord during treatment for childhood leukemia are at a particularly high risk. History of head trauma — Magnetic resonance imaging (MRI) or computed tomography (CT scan) are frequently performed after a head injury. These tests do not increase the risk of developing meningiomas, but instead increases the chance of finding a meningioma that is not causing any symptoms. Exposure to female hormones and breast cancer — Several observations support a link between exposure to female hormones and the risk of meningioma. Meningiomas are more common in women overall, particularly in those who use postmenopausal hormone replacement therapy [3]. In addition, meningiomas may increase in size during pregnancy, a time when female hormones are at their highest levels. There is also a well-described relationship between breast cancer (a tumor that is dependent upon female hormones for growth) and meningioma.
Women with a history of breast cancer have a higher incidence of meningiomas, and women with a history of a meningioma have a greater likelihood of developing breast cancer [4]. Although not proven, these data suggest a shared underlying cause for both tumors.
SYMPTOMS — As noted above, meningiomas may be identified after the patient has an MRI or CT scan for some other reason, such as a head injury. Meningiomas may also be discovered when a person seeks medical attention because he or she is experiencing neurologic symptoms [5]. A variety of symptoms are possible, depending primarily on the location of the meningioma.
Seizures — Seizures (sometimes called "fits") are the result of disorganized electrical activity in the brain. They can cause a person to pass out, involuntarily move the arms and legs, and/or lose muscle control throughout the body. Seizures are also seen in patients with epilepsy and other neurologic disorders. Among patients with meningioma, seizures are the most common presenting symptom and occur in 30 to 40 percent of patients [6].
Neurologic symptoms — Symptoms of a meningioma develop as a result of abnormal functioning of a specific area of the brain. This usually occurs when the tumor presses on normal brain tissue. The symptoms depend upon the location of the meningioma within the brain and the function of that particular area (eg, movement, vision, hearing, sense of balance).
A wide range of symptoms can be seen in patients with meningiomas. Some examples include: Visual changes - Individuals with a meningioma may experience a variety of visual difficulties such as loss of vision in one eye, blind spots, or blurred or double vision. Visual changes may not be noticed by the patient, and may only be noticed as a result of detailed testing. Hearing loss - Meningiomas can cause hearing loss by damaging or compressing the cochlear nerve, which transmits nerve impulses from the ear to the brain. Mental status changes - Patients with large meningiomas on the undersurface of the brain may have subtle changes in their personality or mental status, causing the person to appear that they are not paying attention or are forgetful. Arm and/or leg weakness - A meningioma can cause different patterns of weakness in the arms and legs, depending upon the location of the tumor. As an example, parasagittal meningiomas (ie, tumors located along the separation of the right and left halves of the brain, show figure 1) may cause weakness in both legs. In contrast, tumors arising at the foramen magnum (ie, the location where the base of the brain connects to the spinal cord) may produce a progressive weakness first in the arm and then progresses to involve the leg on the same side, followed by similar changes on the other side of the body.
Obstructive hydrocephalus — As meningiomas grow, they may block the flow of spinal fluid (referred to as obstructive hydrocephalus). Spinal fluid is a clear liquid that is produced within the brain; it functions to fill and protect spaces within and around the brain and spinal cord. If the flow of spinal fluid is blocked, pressure within the head increases. As the pressure on the brain increases, a person may experience headaches (particularly in the morning), nausea, and vomiting. If the condition is untreated, the person may become unable to respond to those around him or her (called a coma).
DIAGNOSIS — If a meningioma is suspected, the clinician will want to obtain a detailed scan of the brain, using either MRI or CT. The major difference between an MRI and CT 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 a tumor and its location.
CT scans are generally more readily available and less expensive than MRI, so a brain CT is often the first test that is ordered. However, MRI is the preferred test if a brain tumor is suspected because it can define more precisely the location and extent of a tumor in the brain or spinal cord (including the meninges), allowing for better treatment planning. Furthermore, the appearance of meningiomas on MRI scanning is unique, meaning that few other types of tumors have a similar appearance. As a result of this unique appearance, a biopsy to confirm that a tumor is a meningioma may not be needed.
In some cases, other disorders need to be ruled out to make a definite diagnosis. As examples, infections (such as tuberculosis), cancers other than meningiomas, and inflammatory diseases (such as sarcoidosis) can cause similar neurologic signs and/or symptoms and thickening of the meninges, making it difficult to determine if a meningioma or another problem is the cause.
TREATMENT — The initial treatment of a meningioma may include surgery, radiation therapy, or careful observation without treatment (sometimes referred to as "conservative management").
Risks versus benefits of treatment — The best approach requires a balance between the potential benefits of treatment (ie, alleviating symptoms and preventing further tumor growth) and the potential side effects and risks of treatment.
Factors that are considered in choosing among different treatment options include: Location of the meningioma — The location of the meningioma determines whether or not the tumor can be removed completely and whether or not blood vessels, nerves, and the underlying brain are likely to be damaged during surgery. As an example, tumors located on the surface of the brain are easiest to remove without risking potentially serious complications.
In contrast, tumors located on the undersurface of the brain or in the groove between the right and left halves of the brain may be more difficult to remove safely. When a tumor cannot be resected by surgery, radiotherapy may be used in conjunction with partial removal of the meningioma. Size of the meningioma — Large tumors are more likely to compress or damage the brain, either directly or by causing swelling of the surrounding normal brain. In contrast, small tumors may not produce symptoms. Thus, patients with larger tumors are more likely to require surgery, even though the operation may be difficult. Symptoms — Tumors that produce symptoms generally require treatment, both to relieve symptoms and prevent their worsening. If a patient is asymptomatic and has no evidence of neurologic dysfunction, careful observation may be appropriate until it can be determined how fast the tumor is growing. Age — Active treatment may not be recommended for older patients with small meningiomas that do not cause symptoms because of the increased risk of serious medical complications following surgery in this age group. In addition, if an older person's tumor is growing slowly, it may never reach a size where it causes symptoms.
In contrast, surgery is more often recommended for younger patients who are less likely to have serious treatment complications. Furthermore, younger patients have a longer life expectancy, and even a slow growing tumor may have time to reach a size where it could cause symptoms. Overall medical condition — Surgery to remove a brain tumor is complex and can be associated with serious complications; this is more likely to occur in patients who have other serious medical conditions.
Surgery — Surgery is the preferred treatment for most meningiomas.
Extent of surgery — Total removal of a meningioma provides the best chance of avoiding a future recurrence. However, the ability to completely remove the tumor depends upon the size and location of the meningioma. Some tumors cannot be totally removed because the tumor is too close or involved with important parts of the brain or blood vessels. In such cases, the tumor may be only partially removed. For tumors near the optic nerve, a small sample of the tumor may be removed so that it can be examined more closely with a microscope.
To improve the chances of completely removing a meningioma, a procedure called embolization may be recommended before surgery. During this procedure, a catheter is carefully placed into the blood vessels leading to or "feeding" the tumor. A material is injected into the blood vessels, which blocks the blood flow. This helps to decrease the risk of serious bleeding during surgery [7].
For tumors that are incompletely removed, the likelihood of recurrence is relatively high, even for grade I tumors. As an example, of 581 patients treated with surgery alone, 75 percent of those undergoing complete removal of a meningioma were free of recurrence 10 years after surgery compared with 39 percent whose tumors had not been completely resected [8].
Following surgery, the risk of tumor recurrence depends upon how much tumor was removed and whether it was cancerous, noncancerous, or atypical. (see "Outcomes" below). For patients whose tumor cannot be removed completely with surgery, radiation therapy is often recommended after surgery to reduce the risk of recurrence (see "Adjuvant radiotherapy" below).
Complications of surgery — Complications associated with surgery include damage to nearby normal brain and medical complications of major surgery (eg, bleeding, infection). Examples of potentially serious complications include: Accumulation of fluid in the brain (cerebral edema) is common after surgery for meningiomas. A corticosteroid medication such as dexamethasone (Decadron) may be given before and after surgery to minimize the extent of cerebral edema. About 20 percent of patients without seizures prior to surgery will develop them after surgery. Thus antiseizure medication is usually recommended following surgery. The medication can usually be slowly discontinued within one week after surgery if seizures do not occur. Worsened or new neurologic symptoms may develop after surgery. Examples of neurologic symptoms include muscle weakness, speech problems, or difficulty with coordination. These symptoms are a result of damage to the brain or other parts of the nervous system, or they may be due to bleeding, cerebral edema, or infection. Medical complications of brain surgery include pneumonia, heart attack, an irregular heart rhythm, or blood clots. Patients who undergo brain surgery or who have brain tumors have an increased risk of blood clots in the veins (deep venous thrombosis) and movement of blood clots to the lungs (pulmonary embolism). As a result, preventive measures are recommended after surgery. This includes use of anticoagulant medications and compression boots (devices that go around the legs and inflate periodically). (See "Patient information: Venous thrombosis").
Radiation therapy — Radiation therapy uses high energy x-rays to damage tumor cells. The x-rays are carefully aimed at the area of the brain affected by the tumor. Unlike normal cells, tumor cells are less able to repair the damage caused by exposure to x-radiation, particularly when the radiation is administered over several days.
Radiation treatment is given in frequent low doses (usually daily treatment, five days per week for 5 to 6 weeks). The total radiation dose is based upon the number of treatments and the amount of radiation administered per treatment. The area of the area of the brain treated is called the treatment field. The total radiation dose and the treatment field are carefully calculated to maximize radiation exposure of tumor cells and minimize damage to the normal brain tissue.
The standard way to deliver radiation is by external beam radiation therapy (EBRT). During EBRT, the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient as he or she lies on a table underneath the machine. The high energy beams are targeted to the area of the brain where the meningioma is located.
Radiation therapy is used for patients who have had partial removal of their meningioma. In addition, radiation may be recommended when surgery is not possible or if surgery has more risks than benefits. As an example, radiation therapy has become the preferred treatment for optic nerve sheath meningiomas (ie, tumors arising in the lining around the nerve to the eye), since there is a lower risk of vision loss after radiation compared to surgery.
Side effects of radiotherapy — A common concern of patients who undergo radiation therapy is treatment-related side effects. Radiation kills both tumor 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 nearby normal brain tissue. Side effects of radiotherapy to the brain can be divided into short term and long term effects. Short term effects — During radiation treatment, hair loss will occur, typically starting around the third or fourth week of therapy. Hair loss is limited to the areas where treatment occurs; this may be temporary or permanent. Regrowth typically begins two to three months after treatment ends. Mild fatigue is common and often does not develop until the last few weeks of radiation treatment. Mild skin redness or irritation may occur and is temporary. Headaches or nausea occur less frequently and can be treated so that they are not persistent. Long term effects — Potential long term effects of RT are more concerning but fortunately less common than short term side effects, especially when modern dosing and treatment plans are used. The most serious long term effect of RT is death of a large number of normal brain cells; this is called radiation necrosis. This may occur many months after the radiation therapy is completed, particularly if high doses are used [6].
Most patients have no symptoms of radiation necrosis. However, patients who have symptoms may have difficulties with short term memory, planning and reaching goals, controlling behavior, paying attention, and organizing thoughts [9]. The risk of these effects depends upon the location and size of the tumor being irradiated and the radiation techniques used; high doses of radiation to a small area are thought to pose a greater risk than lower doses of radiation to larger areas of the brain.
Adjuvant radiotherapy — Use of radiation therapy after partial surgical removal of meningioma is called adjuvant radiotherapy. Adjuvant radiotherapy appears to reduce the risk of recurrence substantially. In one analysis, 77 percent of patients who received adjuvant radiotherapy after a partial surgical removal of a noncancerous meningioma had no recurrence after 10 years [10]. This outcome is similar to that of people who have complete removal of a noncancerous meningioma.
Stereotactic radiosurgery — Stereotactic radiosurgery is an alternative to external beam radiation therapy. This does not actually involve performing surgery, but instead uses narrow beams of radiation that are delivered from multiple angles. This allows a very high dose of radiation to be delivered to a narrow area. This approach may offer substantial advantages to a person with a meningioma because it is able to deliver more radiation to the tumor while minimizing the amount of normal brain that is affected. In contrast to conventional external beam radiation therapy, stereotactic radiosurgery is given as a single treatment.
Stereotactic radiosurgery has been used to deliver adjuvant radiation therapy following partial removal of a meningioma. It has also been used as an alternative to surgery for patients with relatively small meningiomas that cannot be completely removed with surgery. Stereotactic radiosurgery and surgical removal have similar long-term outcomes for patients with small meningiomas [11].
Stereotactic radiotherapy — Stereotactic radiotherapy is slightly different than stereotactic radiosurgery, although both use multiple narrow beams of radiation directed from different angles. However, stereotactic radiotherapy divides the dose into several treatments rather than giving the dose in one single treatment. The intent of stereotactic radiotherapy is to reduce radiation injury to nearby brain structures while maintaining tumor control.
This technique has been particularly useful in meningiomas of the optic nerve sheath, as well as those arising at the base of the skull.
Watchful waiting versus treatment — If a meningioma is small and does not cause symptoms, it may be possible to postpone surgery and/or radiation therapy. The decision to delay treatment is also influenced by the location and size of the tumor, as well as the person's overall medical condition. Treatment is usually considered if there is evidence of tumor growth or if the person develops symptoms.
Watchful waiting requires periodic physical examination along with an imaging test (MRI or CT scan of the head). This is usually recommended every three months for one year, then once per year, assuming that the meningioma does not grow or cause symptoms during this time.
Outcomes do not appear to be worse in patients who are closely monitored. In a review of 60 patients who were diagnosed with small, asymptomatic meningiomas, none developed symptoms during an average of 32 months [12]. Of the 45 patients who had a repeat MRI or CT, 35 had no increase in the size of their tumor, while the remaining 10 showed slow tumor growth, even over the course of up to 15 years.
Systemic therapy — Several treatments, including chemotherapy, hormone therapy, and immunotherapy, have been studied in patients whose tumor recurs after surgery and/or radiation therapy. These treatments are referred to as systemic treatments because they are given by mouth or into a vein and can affect the entire body. The goal of systemic therapy is to slow the growth of the meningioma. The benefits of systemic therapy are usually limited and the treatment is not intended to cure the condition. If possible, re-irradiation or repeat surgery should be considered.
Systemic treatments have been used for patients with malignant meningiomas in an attempt to prevent recurrence. Although initial reports were positive, subsequent studies have not confirmed a benefit. Thus, systemic therapy is usually reserved for treatment of meningiomas that recur after surgery or radiotherapy.
OUTCOMES — The long-term outcome of people with meningioma depends upon several factors. For patients who require treatment of symptomatic or large meningiomas, the outcome depends upon the completeness of surgery and the meningioma type (ie, benign, atypical, or malignant). It is important to remember that discussions of outcomes are based upon averages; these averages do not necessarily predict how long an individual patient will survive. Small meningiomas that cause no symptoms and do not require treatment do not usually shorten a person's life. Complete resection of the tumor is possible in about 80 percent of patients with benign meningiomas, approximately 70 to 80 percent of whom survive at least ten years without a recurrence. For patients whose tumors cannot be completely removed and those with cancerous tumors, the rate of recurrence is markedly increased. However, the use of radiation therapy after surgery has improved outcomes, and the risk of recurrence may be similar to patients whose tumor is completely resected. Cancerous (malignant) meningiomas are much more likely to recur, even after complete surgical removal. Recurrence rates are somewhat lower after removal of atypical meningiomas, although recurrence is more frequent than in people who have surgical removal of a benign meningioma. The benefit of postoperative radiation is controversial in these patients.
CLINICAL TRIALS — Progress in treating meningioma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are conducted in many countries around the world. 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 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. American Brain Tumor Association
(www.abta.org)
American Cancer Society
(www.cancer.org)
National Cancer Institute
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
OncoLink
(www.oncolink.com/index.cfm)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Claus, EB, Bondy, ML, Schildkraut, JM, et al. Epidemiology of intracranial meningioma. Neurosurgery 2005; 57:1088.
2. Palma, L, Celli, P, Franco, C, et al. Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 1997; 86:793.
3. Jhawar, BS, Fuchs, CS, Colditz, GA, Stampfer, MJ. Sex steroid hormone exposures and risk for meningioma. J Neurosurg 2003; 99:848.
4. Custer, BS, Koepsell, TD, Mueller, BA. The association between breast carcinoma and meningioma in women. Cancer 2002; 94:1626.
5. Nakamura, M, Roser, F, Michel, J, et al. The natural history of incidental meningiomas. Neurosurgery 2003; 53:62.
6. Lieu, AS, Howng, SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000; 38:45.
7. Rosen, CL, Ammerman, JM, Sekhar, LN, Bank, WO. Outcome analysis of preoperative embolization in cranial base surgery. Acta Neurochir (Wien) 2002; 144:1157.
8. Stafford, SL, Perry, A, Suman, VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc 1998; 73:936.
9. Armstrong CL, Gyato K, Awadalla AW, Lustig, R, Tochner, ZA. A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev 2004; 14:65.
10. Goldsmith, BJ, Wara, WM, Wilson, CB, Larson, DA. Post-operative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994; 80:195.
11. Pollock, BE, Stafford, SL, Utter, A, et al. Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 2003; 55:1000.
12. Olivero, WC, Lister, JR, Elwood, PW. The natural history and growth rate of asymptomatic meningiomas: a review of 60 patients. J Neurosurg 1995; 83:222.
Friday, October 12, 2007
Brain tumors Patient information: Meningioma
INTRODUCTION — Meningiomas are brain tumors that develop in the tissue that surrounds and protects the outer surface of the brain and spinal cord (the meninges). Meningiomas account for about 15 to 30 percent of all tumors that originate in the brain. They are seen most frequently after age 40, and are more common in women than men [1].
Meningiomas can occur in any part of the lining over the brain or spinal cord (show figure 1). About 90 percent occur within the head: around the cerebral hemispheres (just inside the skull), on the under surface of the brain (at the base of the skull), or in the lower part of the brain (the brainstem, which is located just above the spinal cord). Most of the remaining meningiomas arise in the optic nerve sheath (which protects the nerve connecting the eye to the brain) and around the spinal cord.
CLASSIFICATION OF MENINGIOMA — Meningiomas are classified according to their appearance when examined under the microscope and their position in the brain. Microscopic examination provides information about the cells comprising the meningioma, including how rapidly the cells are dividing (referred to as the "mitotic index") and whether the meningioma cells are growing into or invading the adjacent normal brain. Classification provides valuable information about the likelihood of meningioma returning ("recurring") after treatment.
The most widely used classification system is that of the World Health Organization (WHO), which separates meningiomas into three categories:
Grade I or benign meningiomas — Benign meningiomas are slow-growing tumors that have well-defined borders and do not appear to invade the adjacent normal brain. Few meningioma cells are actively dividing (ie, the tumor has a low mitotic index). Approximately 90 percent of all meningiomas fall into this category.
Grade II or atypical meningiomas — Atypical meningiomas contain more cells that are actively dividing (ie, they have a higher mitotic index) than benign meningiomas. In addition, grade II tumors have other features that suggest that they are growing more rapidly than benign meningiomas. These lesions are more likely to recur than benign tumors. Atypical meningiomas constitute about 5 to 7 percent of all meningiomas.
Grade III or malignant meningiomas — Malignant meningiomas, which are sometimes referred to as anaplastic meningiomas, have the highest mitotic index. Malignant meningiomas are likely to recur after treatment. These comprise 1 to 3 percent of all meningiomas.
A higher grade correlates with a worse prognosis. Patients with benign (grade I) meningiomas generally do well, with 80 percent or more remaining free of progression or recurrence after their initial treatment. In contrast, patients with atypical (grade II) and malignant (grade III) meningiomas are at much higher risk for recurrence. In one report, patients with atypical meningiomas had recurrence within an average of five years, while patients with malignant meningiomas had recurrence within an average of only two years [2].
RISK FACTORS — The cause of meningiomas is not well understood, but may include both genetic (inherited) and environmental factors. Several conditions have been associated with an increased risk for the development of a meningioma [1]: Neurofibromatosis - Neurofibromatosis type 2 is a rare inherited disease that usually appears first during childhood. This disorder affects the skin and the nervous system, and increases the risk of meningiomas as well as other brain tumors. Affected patients may develop multiple meningiomas. Previous radiation therapy treatment - Patients who have had radiation exposure to the head have an increased risk for developing a meningioma, especially 10 to 20 years after treatment. Individuals who underwent irradiation of the brain and spinal cord during treatment for childhood leukemia are at a particularly high risk. History of head trauma — Magnetic resonance imaging (MRI) or computed tomography (CT scan) are frequently performed after a head injury. These tests do not increase the risk of developing meningiomas, but instead increases the chance of finding a meningioma that is not causing any symptoms. Exposure to female hormones and breast cancer — Several observations support a link between exposure to female hormones and the risk of meningioma. Meningiomas are more common in women overall, particularly in those who use postmenopausal hormone replacement therapy [3]. In addition, meningiomas may increase in size during pregnancy, a time when female hormones are at their highest levels. There is also a well-described relationship between breast cancer (a tumor that is dependent upon female hormones for growth) and meningioma.
Women with a history of breast cancer have a higher incidence of meningiomas, and women with a history of a meningioma have a greater likelihood of developing breast cancer [4]. Although not proven, these data suggest a shared underlying cause for both tumors.
SYMPTOMS — As noted above, meningiomas may be identified after the patient has an MRI or CT scan for some other reason, such as a head injury. Meningiomas may also be discovered when a person seeks medical attention because he or she is experiencing neurologic symptoms [5]. A variety of symptoms are possible, depending primarily on the location of the meningioma.
Seizures — Seizures (sometimes called "fits") are the result of disorganized electrical activity in the brain. They can cause a person to pass out, involuntarily move the arms and legs, and/or lose muscle control throughout the body. Seizures are also seen in patients with epilepsy and other neurologic disorders. Among patients with meningioma, seizures are the most common presenting symptom and occur in 30 to 40 percent of patients [6].
Neurologic symptoms — Symptoms of a meningioma develop as a result of abnormal functioning of a specific area of the brain. This usually occurs when the tumor presses on normal brain tissue. The symptoms depend upon the location of the meningioma within the brain and the function of that particular area (eg, movement, vision, hearing, sense of balance).
A wide range of symptoms can be seen in patients with meningiomas. Some examples include: Visual changes - Individuals with a meningioma may experience a variety of visual difficulties such as loss of vision in one eye, blind spots, or blurred or double vision. Visual changes may not be noticed by the patient, and may only be noticed as a result of detailed testing. Hearing loss - Meningiomas can cause hearing loss by damaging or compressing the cochlear nerve, which transmits nerve impulses from the ear to the brain. Mental status changes - Patients with large meningiomas on the undersurface of the brain may have subtle changes in their personality or mental status, causing the person to appear that they are not paying attention or are forgetful. Arm and/or leg weakness - A meningioma can cause different patterns of weakness in the arms and legs, depending upon the location of the tumor. As an example, parasagittal meningiomas (ie, tumors located along the separation of the right and left halves of the brain, show figure 1) may cause weakness in both legs. In contrast, tumors arising at the foramen magnum (ie, the location where the base of the brain connects to the spinal cord) may produce a progressive weakness first in the arm and then progresses to involve the leg on the same side, followed by similar changes on the other side of the body.
Obstructive hydrocephalus — As meningiomas grow, they may block the flow of spinal fluid (referred to as obstructive hydrocephalus). Spinal fluid is a clear liquid that is produced within the brain; it functions to fill and protect spaces within and around the brain and spinal cord. If the flow of spinal fluid is blocked, pressure within the head increases. As the pressure on the brain increases, a person may experience headaches (particularly in the morning), nausea, and vomiting. If the condition is untreated, the person may become unable to respond to those around him or her (called a coma).
DIAGNOSIS — If a meningioma is suspected, the clinician will want to obtain a detailed scan of the brain, using either MRI or CT. The major difference between an MRI and CT 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 a tumor and its location.
CT scans are generally more readily available and less expensive than MRI, so a brain CT is often the first test that is ordered. However, MRI is the preferred test if a brain tumor is suspected because it can define more precisely the location and extent of a tumor in the brain or spinal cord (including the meninges), allowing for better treatment planning. Furthermore, the appearance of meningiomas on MRI scanning is unique, meaning that few other types of tumors have a similar appearance. As a result of this unique appearance, a biopsy to confirm that a tumor is a meningioma may not be needed.
In some cases, other disorders need to be ruled out to make a definite diagnosis. As examples, infections (such as tuberculosis), cancers other than meningiomas, and inflammatory diseases (such as sarcoidosis) can cause similar neurologic signs and/or symptoms and thickening of the meninges, making it difficult to determine if a meningioma or another problem is the cause.
TREATMENT — The initial treatment of a meningioma may include surgery, radiation therapy, or careful observation without treatment (sometimes referred to as "conservative management").
Risks versus benefits of treatment — The best approach requires a balance between the potential benefits of treatment (ie, alleviating symptoms and preventing further tumor growth) and the potential side effects and risks of treatment.
Factors that are considered in choosing among different treatment options include: Location of the meningioma — The location of the meningioma determines whether or not the tumor can be removed completely and whether or not blood vessels, nerves, and the underlying brain are likely to be damaged during surgery. As an example, tumors located on the surface of the brain are easiest to remove without risking potentially serious complications.
In contrast, tumors located on the undersurface of the brain or in the groove between the right and left halves of the brain may be more difficult to remove safely. When a tumor cannot be resected by surgery, radiotherapy may be used in conjunction with partial removal of the meningioma. Size of the meningioma — Large tumors are more likely to compress or damage the brain, either directly or by causing swelling of the surrounding normal brain. In contrast, small tumors may not produce symptoms. Thus, patients with larger tumors are more likely to require surgery, even though the operation may be difficult. Symptoms — Tumors that produce symptoms generally require treatment, both to relieve symptoms and prevent their worsening. If a patient is asymptomatic and has no evidence of neurologic dysfunction, careful observation may be appropriate until it can be determined how fast the tumor is growing. Age — Active treatment may not be recommended for older patients with small meningiomas that do not cause symptoms because of the increased risk of serious medical complications following surgery in this age group. In addition, if an older person's tumor is growing slowly, it may never reach a size where it causes symptoms.
In contrast, surgery is more often recommended for younger patients who are less likely to have serious treatment complications. Furthermore, younger patients have a longer life expectancy, and even a slow growing tumor may have time to reach a size where it could cause symptoms. Overall medical condition — Surgery to remove a brain tumor is complex and can be associated with serious complications; this is more likely to occur in patients who have other serious medical conditions.
Surgery — Surgery is the preferred treatment for most meningiomas.
Extent of surgery — Total removal of a meningioma provides the best chance of avoiding a future recurrence. However, the ability to completely remove the tumor depends upon the size and location of the meningioma. Some tumors cannot be totally removed because the tumor is too close or involved with important parts of the brain or blood vessels. In such cases, the tumor may be only partially removed. For tumors near the optic nerve, a small sample of the tumor may be removed so that it can be examined more closely with a microscope.
To improve the chances of completely removing a meningioma, a procedure called embolization may be recommended before surgery. During this procedure, a catheter is carefully placed into the blood vessels leading to or "feeding" the tumor. A material is injected into the blood vessels, which blocks the blood flow. This helps to decrease the risk of serious bleeding during surgery [7].
For tumors that are incompletely removed, the likelihood of recurrence is relatively high, even for grade I tumors. As an example, of 581 patients treated with surgery alone, 75 percent of those undergoing complete removal of a meningioma were free of recurrence 10 years after surgery compared with 39 percent whose tumors had not been completely resected [8].
Following surgery, the risk of tumor recurrence depends upon how much tumor was removed and whether it was cancerous, noncancerous, or atypical. (see "Outcomes" below). For patients whose tumor cannot be removed completely with surgery, radiation therapy is often recommended after surgery to reduce the risk of recurrence (see "Adjuvant radiotherapy" below).
Complications of surgery — Complications associated with surgery include damage to nearby normal brain and medical complications of major surgery (eg, bleeding, infection). Examples of potentially serious complications include: Accumulation of fluid in the brain (cerebral edema) is common after surgery for meningiomas. A corticosteroid medication such as dexamethasone (Decadron) may be given before and after surgery to minimize the extent of cerebral edema. About 20 percent of patients without seizures prior to surgery will develop them after surgery. Thus antiseizure medication is usually recommended following surgery. The medication can usually be slowly discontinued within one week after surgery if seizures do not occur. Worsened or new neurologic symptoms may develop after surgery. Examples of neurologic symptoms include muscle weakness, speech problems, or difficulty with coordination. These symptoms are a result of damage to the brain or other parts of the nervous system, or they may be due to bleeding, cerebral edema, or infection. Medical complications of brain surgery include pneumonia, heart attack, an irregular heart rhythm, or blood clots. Patients who undergo brain surgery or who have brain tumors have an increased risk of blood clots in the veins (deep venous thrombosis) and movement of blood clots to the lungs (pulmonary embolism). As a result, preventive measures are recommended after surgery. This includes use of anticoagulant medications and compression boots (devices that go around the legs and inflate periodically). (See "Patient information: Venous thrombosis").
Radiation therapy — Radiation therapy uses high energy x-rays to damage tumor cells. The x-rays are carefully aimed at the area of the brain affected by the tumor. Unlike normal cells, tumor cells are less able to repair the damage caused by exposure to x-radiation, particularly when the radiation is administered over several days.
Radiation treatment is given in frequent low doses (usually daily treatment, five days per week for 5 to 6 weeks). The total radiation dose is based upon the number of treatments and the amount of radiation administered per treatment. The area of the area of the brain treated is called the treatment field. The total radiation dose and the treatment field are carefully calculated to maximize radiation exposure of tumor cells and minimize damage to the normal brain tissue.
The standard way to deliver radiation is by external beam radiation therapy (EBRT). During EBRT, the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient as he or she lies on a table underneath the machine. The high energy beams are targeted to the area of the brain where the meningioma is located.
Radiation therapy is used for patients who have had partial removal of their meningioma. In addition, radiation may be recommended when surgery is not possible or if surgery has more risks than benefits. As an example, radiation therapy has become the preferred treatment for optic nerve sheath meningiomas (ie, tumors arising in the lining around the nerve to the eye), since there is a lower risk of vision loss after radiation compared to surgery.
Side effects of radiotherapy — A common concern of patients who undergo radiation therapy is treatment-related side effects. Radiation kills both tumor 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 nearby normal brain tissue. Side effects of radiotherapy to the brain can be divided into short term and long term effects. Short term effects — During radiation treatment, hair loss will occur, typically starting around the third or fourth week of therapy. Hair loss is limited to the areas where treatment occurs; this may be temporary or permanent. Regrowth typically begins two to three months after treatment ends. Mild fatigue is common and often does not develop until the last few weeks of radiation treatment. Mild skin redness or irritation may occur and is temporary. Headaches or nausea occur less frequently and can be treated so that they are not persistent. Long term effects — Potential long term effects of RT are more concerning but fortunately less common than short term side effects, especially when modern dosing and treatment plans are used. The most serious long term effect of RT is death of a large number of normal brain cells; this is called radiation necrosis. This may occur many months after the radiation therapy is completed, particularly if high doses are used [6].
Most patients have no symptoms of radiation necrosis. However, patients who have symptoms may have difficulties with short term memory, planning and reaching goals, controlling behavior, paying attention, and organizing thoughts [9]. The risk of these effects depends upon the location and size of the tumor being irradiated and the radiation techniques used; high doses of radiation to a small area are thought to pose a greater risk than lower doses of radiation to larger areas of the brain.
Adjuvant radiotherapy — Use of radiation therapy after partial surgical removal of meningioma is called adjuvant radiotherapy. Adjuvant radiotherapy appears to reduce the risk of recurrence substantially. In one analysis, 77 percent of patients who received adjuvant radiotherapy after a partial surgical removal of a noncancerous meningioma had no recurrence after 10 years [10]. This outcome is similar to that of people who have complete removal of a noncancerous meningioma.
Stereotactic radiosurgery — Stereotactic radiosurgery is an alternative to external beam radiation therapy. This does not actually involve performing surgery, but instead uses narrow beams of radiation that are delivered from multiple angles. This allows a very high dose of radiation to be delivered to a narrow area. This approach may offer substantial advantages to a person with a meningioma because it is able to deliver more radiation to the tumor while minimizing the amount of normal brain that is affected. In contrast to conventional external beam radiation therapy, stereotactic radiosurgery is given as a single treatment.
Stereotactic radiosurgery has been used to deliver adjuvant radiation therapy following partial removal of a meningioma. It has also been used as an alternative to surgery for patients with relatively small meningiomas that cannot be completely removed with surgery. Stereotactic radiosurgery and surgical removal have similar long-term outcomes for patients with small meningiomas [11].
Stereotactic radiotherapy — Stereotactic radiotherapy is slightly different than stereotactic radiosurgery, although both use multiple narrow beams of radiation directed from different angles. However, stereotactic radiotherapy divides the dose into several treatments rather than giving the dose in one single treatment. The intent of stereotactic radiotherapy is to reduce radiation injury to nearby brain structures while maintaining tumor control.
This technique has been particularly useful in meningiomas of the optic nerve sheath, as well as those arising at the base of the skull.
Watchful waiting versus treatment — If a meningioma is small and does not cause symptoms, it may be possible to postpone surgery and/or radiation therapy. The decision to delay treatment is also influenced by the location and size of the tumor, as well as the person's overall medical condition. Treatment is usually considered if there is evidence of tumor growth or if the person develops symptoms.
Watchful waiting requires periodic physical examination along with an imaging test (MRI or CT scan of the head). This is usually recommended every three months for one year, then once per year, assuming that the meningioma does not grow or cause symptoms during this time.
Outcomes do not appear to be worse in patients who are closely monitored. In a review of 60 patients who were diagnosed with small, asymptomatic meningiomas, none developed symptoms during an average of 32 months [12]. Of the 45 patients who had a repeat MRI or CT, 35 had no increase in the size of their tumor, while the remaining 10 showed slow tumor growth, even over the course of up to 15 years.
Systemic therapy — Several treatments, including chemotherapy, hormone therapy, and immunotherapy, have been studied in patients whose tumor recurs after surgery and/or radiation therapy. These treatments are referred to as systemic treatments because they are given by mouth or into a vein and can affect the entire body. The goal of systemic therapy is to slow the growth of the meningioma. The benefits of systemic therapy are usually limited and the treatment is not intended to cure the condition. If possible, re-irradiation or repeat surgery should be considered.
Systemic treatments have been used for patients with malignant meningiomas in an attempt to prevent recurrence. Although initial reports were positive, subsequent studies have not confirmed a benefit. Thus, systemic therapy is usually reserved for treatment of meningiomas that recur after surgery or radiotherapy.
OUTCOMES — The long-term outcome of people with meningioma depends upon several factors. For patients who require treatment of symptomatic or large meningiomas, the outcome depends upon the completeness of surgery and the meningioma type (ie, benign, atypical, or malignant). It is important to remember that discussions of outcomes are based upon averages; these averages do not necessarily predict how long an individual patient will survive. Small meningiomas that cause no symptoms and do not require treatment do not usually shorten a person's life. Complete resection of the tumor is possible in about 80 percent of patients with benign meningiomas, approximately 70 to 80 percent of whom survive at least ten years without a recurrence. For patients whose tumors cannot be completely removed and those with cancerous tumors, the rate of recurrence is markedly increased. However, the use of radiation therapy after surgery has improved outcomes, and the risk of recurrence may be similar to patients whose tumor is completely resected. Cancerous (malignant) meningiomas are much more likely to recur, even after complete surgical removal. Recurrence rates are somewhat lower after removal of atypical meningiomas, although recurrence is more frequent than in people who have surgical removal of a benign meningioma. The benefit of postoperative radiation is controversial in these patients.
CLINICAL TRIALS — Progress in treating meningioma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are conducted in many countries around the world. 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 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. American Brain Tumor Association
(www.abta.org)
American Cancer Society
(www.cancer.org)
National Cancer Institute
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
OncoLink
(www.oncolink.com/index.cfm)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Claus, EB, Bondy, ML, Schildkraut, JM, et al. Epidemiology of intracranial meningioma. Neurosurgery 2005; 57:1088.
2. Palma, L, Celli, P, Franco, C, et al. Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 1997; 86:793.
3. Jhawar, BS, Fuchs, CS, Colditz, GA, Stampfer, MJ. Sex steroid hormone exposures and risk for meningioma. J Neurosurg 2003; 99:848.
4. Custer, BS, Koepsell, TD, Mueller, BA. The association between breast carcinoma and meningioma in women. Cancer 2002; 94:1626.
5. Nakamura, M, Roser, F, Michel, J, et al. The natural history of incidental meningiomas. Neurosurgery 2003; 53:62.
6. Lieu, AS, Howng, SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000; 38:45.
7. Rosen, CL, Ammerman, JM, Sekhar, LN, Bank, WO. Outcome analysis of preoperative embolization in cranial base surgery. Acta Neurochir (Wien) 2002; 144:1157.
8. Stafford, SL, Perry, A, Suman, VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc 1998; 73:936.
9. Armstrong CL, Gyato K, Awadalla AW, Lustig, R, Tochner, ZA. A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev 2004; 14:65.
10. Goldsmith, BJ, Wara, WM, Wilson, CB, Larson, DA. Post-operative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994; 80:195.
11. Pollock, BE, Stafford, SL, Utter, A, et al. Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 2003; 55:1000.
12. Olivero, WC, Lister, JR, Elwood, PW. The natural history and growth rate of asymptomatic meningiomas: a review of 60 patients. J Neurosurg 1995; 83:222.
Meningiomas can occur in any part of the lining over the brain or spinal cord (show figure 1). About 90 percent occur within the head: around the cerebral hemispheres (just inside the skull), on the under surface of the brain (at the base of the skull), or in the lower part of the brain (the brainstem, which is located just above the spinal cord). Most of the remaining meningiomas arise in the optic nerve sheath (which protects the nerve connecting the eye to the brain) and around the spinal cord.
CLASSIFICATION OF MENINGIOMA — Meningiomas are classified according to their appearance when examined under the microscope and their position in the brain. Microscopic examination provides information about the cells comprising the meningioma, including how rapidly the cells are dividing (referred to as the "mitotic index") and whether the meningioma cells are growing into or invading the adjacent normal brain. Classification provides valuable information about the likelihood of meningioma returning ("recurring") after treatment.
The most widely used classification system is that of the World Health Organization (WHO), which separates meningiomas into three categories:
Grade I or benign meningiomas — Benign meningiomas are slow-growing tumors that have well-defined borders and do not appear to invade the adjacent normal brain. Few meningioma cells are actively dividing (ie, the tumor has a low mitotic index). Approximately 90 percent of all meningiomas fall into this category.
Grade II or atypical meningiomas — Atypical meningiomas contain more cells that are actively dividing (ie, they have a higher mitotic index) than benign meningiomas. In addition, grade II tumors have other features that suggest that they are growing more rapidly than benign meningiomas. These lesions are more likely to recur than benign tumors. Atypical meningiomas constitute about 5 to 7 percent of all meningiomas.
Grade III or malignant meningiomas — Malignant meningiomas, which are sometimes referred to as anaplastic meningiomas, have the highest mitotic index. Malignant meningiomas are likely to recur after treatment. These comprise 1 to 3 percent of all meningiomas.
A higher grade correlates with a worse prognosis. Patients with benign (grade I) meningiomas generally do well, with 80 percent or more remaining free of progression or recurrence after their initial treatment. In contrast, patients with atypical (grade II) and malignant (grade III) meningiomas are at much higher risk for recurrence. In one report, patients with atypical meningiomas had recurrence within an average of five years, while patients with malignant meningiomas had recurrence within an average of only two years [2].
RISK FACTORS — The cause of meningiomas is not well understood, but may include both genetic (inherited) and environmental factors. Several conditions have been associated with an increased risk for the development of a meningioma [1]: Neurofibromatosis - Neurofibromatosis type 2 is a rare inherited disease that usually appears first during childhood. This disorder affects the skin and the nervous system, and increases the risk of meningiomas as well as other brain tumors. Affected patients may develop multiple meningiomas. Previous radiation therapy treatment - Patients who have had radiation exposure to the head have an increased risk for developing a meningioma, especially 10 to 20 years after treatment. Individuals who underwent irradiation of the brain and spinal cord during treatment for childhood leukemia are at a particularly high risk. History of head trauma — Magnetic resonance imaging (MRI) or computed tomography (CT scan) are frequently performed after a head injury. These tests do not increase the risk of developing meningiomas, but instead increases the chance of finding a meningioma that is not causing any symptoms. Exposure to female hormones and breast cancer — Several observations support a link between exposure to female hormones and the risk of meningioma. Meningiomas are more common in women overall, particularly in those who use postmenopausal hormone replacement therapy [3]. In addition, meningiomas may increase in size during pregnancy, a time when female hormones are at their highest levels. There is also a well-described relationship between breast cancer (a tumor that is dependent upon female hormones for growth) and meningioma.
Women with a history of breast cancer have a higher incidence of meningiomas, and women with a history of a meningioma have a greater likelihood of developing breast cancer [4]. Although not proven, these data suggest a shared underlying cause for both tumors.
SYMPTOMS — As noted above, meningiomas may be identified after the patient has an MRI or CT scan for some other reason, such as a head injury. Meningiomas may also be discovered when a person seeks medical attention because he or she is experiencing neurologic symptoms [5]. A variety of symptoms are possible, depending primarily on the location of the meningioma.
Seizures — Seizures (sometimes called "fits") are the result of disorganized electrical activity in the brain. They can cause a person to pass out, involuntarily move the arms and legs, and/or lose muscle control throughout the body. Seizures are also seen in patients with epilepsy and other neurologic disorders. Among patients with meningioma, seizures are the most common presenting symptom and occur in 30 to 40 percent of patients [6].
Neurologic symptoms — Symptoms of a meningioma develop as a result of abnormal functioning of a specific area of the brain. This usually occurs when the tumor presses on normal brain tissue. The symptoms depend upon the location of the meningioma within the brain and the function of that particular area (eg, movement, vision, hearing, sense of balance).
A wide range of symptoms can be seen in patients with meningiomas. Some examples include: Visual changes - Individuals with a meningioma may experience a variety of visual difficulties such as loss of vision in one eye, blind spots, or blurred or double vision. Visual changes may not be noticed by the patient, and may only be noticed as a result of detailed testing. Hearing loss - Meningiomas can cause hearing loss by damaging or compressing the cochlear nerve, which transmits nerve impulses from the ear to the brain. Mental status changes - Patients with large meningiomas on the undersurface of the brain may have subtle changes in their personality or mental status, causing the person to appear that they are not paying attention or are forgetful. Arm and/or leg weakness - A meningioma can cause different patterns of weakness in the arms and legs, depending upon the location of the tumor. As an example, parasagittal meningiomas (ie, tumors located along the separation of the right and left halves of the brain, show figure 1) may cause weakness in both legs. In contrast, tumors arising at the foramen magnum (ie, the location where the base of the brain connects to the spinal cord) may produce a progressive weakness first in the arm and then progresses to involve the leg on the same side, followed by similar changes on the other side of the body.
Obstructive hydrocephalus — As meningiomas grow, they may block the flow of spinal fluid (referred to as obstructive hydrocephalus). Spinal fluid is a clear liquid that is produced within the brain; it functions to fill and protect spaces within and around the brain and spinal cord. If the flow of spinal fluid is blocked, pressure within the head increases. As the pressure on the brain increases, a person may experience headaches (particularly in the morning), nausea, and vomiting. If the condition is untreated, the person may become unable to respond to those around him or her (called a coma).
DIAGNOSIS — If a meningioma is suspected, the clinician will want to obtain a detailed scan of the brain, using either MRI or CT. The major difference between an MRI and CT 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 a tumor and its location.
CT scans are generally more readily available and less expensive than MRI, so a brain CT is often the first test that is ordered. However, MRI is the preferred test if a brain tumor is suspected because it can define more precisely the location and extent of a tumor in the brain or spinal cord (including the meninges), allowing for better treatment planning. Furthermore, the appearance of meningiomas on MRI scanning is unique, meaning that few other types of tumors have a similar appearance. As a result of this unique appearance, a biopsy to confirm that a tumor is a meningioma may not be needed.
In some cases, other disorders need to be ruled out to make a definite diagnosis. As examples, infections (such as tuberculosis), cancers other than meningiomas, and inflammatory diseases (such as sarcoidosis) can cause similar neurologic signs and/or symptoms and thickening of the meninges, making it difficult to determine if a meningioma or another problem is the cause.
TREATMENT — The initial treatment of a meningioma may include surgery, radiation therapy, or careful observation without treatment (sometimes referred to as "conservative management").
Risks versus benefits of treatment — The best approach requires a balance between the potential benefits of treatment (ie, alleviating symptoms and preventing further tumor growth) and the potential side effects and risks of treatment.
Factors that are considered in choosing among different treatment options include: Location of the meningioma — The location of the meningioma determines whether or not the tumor can be removed completely and whether or not blood vessels, nerves, and the underlying brain are likely to be damaged during surgery. As an example, tumors located on the surface of the brain are easiest to remove without risking potentially serious complications.
In contrast, tumors located on the undersurface of the brain or in the groove between the right and left halves of the brain may be more difficult to remove safely. When a tumor cannot be resected by surgery, radiotherapy may be used in conjunction with partial removal of the meningioma. Size of the meningioma — Large tumors are more likely to compress or damage the brain, either directly or by causing swelling of the surrounding normal brain. In contrast, small tumors may not produce symptoms. Thus, patients with larger tumors are more likely to require surgery, even though the operation may be difficult. Symptoms — Tumors that produce symptoms generally require treatment, both to relieve symptoms and prevent their worsening. If a patient is asymptomatic and has no evidence of neurologic dysfunction, careful observation may be appropriate until it can be determined how fast the tumor is growing. Age — Active treatment may not be recommended for older patients with small meningiomas that do not cause symptoms because of the increased risk of serious medical complications following surgery in this age group. In addition, if an older person's tumor is growing slowly, it may never reach a size where it causes symptoms.
In contrast, surgery is more often recommended for younger patients who are less likely to have serious treatment complications. Furthermore, younger patients have a longer life expectancy, and even a slow growing tumor may have time to reach a size where it could cause symptoms. Overall medical condition — Surgery to remove a brain tumor is complex and can be associated with serious complications; this is more likely to occur in patients who have other serious medical conditions.
Surgery — Surgery is the preferred treatment for most meningiomas.
Extent of surgery — Total removal of a meningioma provides the best chance of avoiding a future recurrence. However, the ability to completely remove the tumor depends upon the size and location of the meningioma. Some tumors cannot be totally removed because the tumor is too close or involved with important parts of the brain or blood vessels. In such cases, the tumor may be only partially removed. For tumors near the optic nerve, a small sample of the tumor may be removed so that it can be examined more closely with a microscope.
To improve the chances of completely removing a meningioma, a procedure called embolization may be recommended before surgery. During this procedure, a catheter is carefully placed into the blood vessels leading to or "feeding" the tumor. A material is injected into the blood vessels, which blocks the blood flow. This helps to decrease the risk of serious bleeding during surgery [7].
For tumors that are incompletely removed, the likelihood of recurrence is relatively high, even for grade I tumors. As an example, of 581 patients treated with surgery alone, 75 percent of those undergoing complete removal of a meningioma were free of recurrence 10 years after surgery compared with 39 percent whose tumors had not been completely resected [8].
Following surgery, the risk of tumor recurrence depends upon how much tumor was removed and whether it was cancerous, noncancerous, or atypical. (see "Outcomes" below). For patients whose tumor cannot be removed completely with surgery, radiation therapy is often recommended after surgery to reduce the risk of recurrence (see "Adjuvant radiotherapy" below).
Complications of surgery — Complications associated with surgery include damage to nearby normal brain and medical complications of major surgery (eg, bleeding, infection). Examples of potentially serious complications include: Accumulation of fluid in the brain (cerebral edema) is common after surgery for meningiomas. A corticosteroid medication such as dexamethasone (Decadron) may be given before and after surgery to minimize the extent of cerebral edema. About 20 percent of patients without seizures prior to surgery will develop them after surgery. Thus antiseizure medication is usually recommended following surgery. The medication can usually be slowly discontinued within one week after surgery if seizures do not occur. Worsened or new neurologic symptoms may develop after surgery. Examples of neurologic symptoms include muscle weakness, speech problems, or difficulty with coordination. These symptoms are a result of damage to the brain or other parts of the nervous system, or they may be due to bleeding, cerebral edema, or infection. Medical complications of brain surgery include pneumonia, heart attack, an irregular heart rhythm, or blood clots. Patients who undergo brain surgery or who have brain tumors have an increased risk of blood clots in the veins (deep venous thrombosis) and movement of blood clots to the lungs (pulmonary embolism). As a result, preventive measures are recommended after surgery. This includes use of anticoagulant medications and compression boots (devices that go around the legs and inflate periodically). (See "Patient information: Venous thrombosis").
Radiation therapy — Radiation therapy uses high energy x-rays to damage tumor cells. The x-rays are carefully aimed at the area of the brain affected by the tumor. Unlike normal cells, tumor cells are less able to repair the damage caused by exposure to x-radiation, particularly when the radiation is administered over several days.
Radiation treatment is given in frequent low doses (usually daily treatment, five days per week for 5 to 6 weeks). The total radiation dose is based upon the number of treatments and the amount of radiation administered per treatment. The area of the area of the brain treated is called the treatment field. The total radiation dose and the treatment field are carefully calculated to maximize radiation exposure of tumor cells and minimize damage to the normal brain tissue.
The standard way to deliver radiation is by external beam radiation therapy (EBRT). During EBRT, the radiation beam is generated by a machine that is outside the patient. The radiation is delivered to the patient as he or she lies on a table underneath the machine. The high energy beams are targeted to the area of the brain where the meningioma is located.
Radiation therapy is used for patients who have had partial removal of their meningioma. In addition, radiation may be recommended when surgery is not possible or if surgery has more risks than benefits. As an example, radiation therapy has become the preferred treatment for optic nerve sheath meningiomas (ie, tumors arising in the lining around the nerve to the eye), since there is a lower risk of vision loss after radiation compared to surgery.
Side effects of radiotherapy — A common concern of patients who undergo radiation therapy is treatment-related side effects. Radiation kills both tumor 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 nearby normal brain tissue. Side effects of radiotherapy to the brain can be divided into short term and long term effects. Short term effects — During radiation treatment, hair loss will occur, typically starting around the third or fourth week of therapy. Hair loss is limited to the areas where treatment occurs; this may be temporary or permanent. Regrowth typically begins two to three months after treatment ends. Mild fatigue is common and often does not develop until the last few weeks of radiation treatment. Mild skin redness or irritation may occur and is temporary. Headaches or nausea occur less frequently and can be treated so that they are not persistent. Long term effects — Potential long term effects of RT are more concerning but fortunately less common than short term side effects, especially when modern dosing and treatment plans are used. The most serious long term effect of RT is death of a large number of normal brain cells; this is called radiation necrosis. This may occur many months after the radiation therapy is completed, particularly if high doses are used [6].
Most patients have no symptoms of radiation necrosis. However, patients who have symptoms may have difficulties with short term memory, planning and reaching goals, controlling behavior, paying attention, and organizing thoughts [9]. The risk of these effects depends upon the location and size of the tumor being irradiated and the radiation techniques used; high doses of radiation to a small area are thought to pose a greater risk than lower doses of radiation to larger areas of the brain.
Adjuvant radiotherapy — Use of radiation therapy after partial surgical removal of meningioma is called adjuvant radiotherapy. Adjuvant radiotherapy appears to reduce the risk of recurrence substantially. In one analysis, 77 percent of patients who received adjuvant radiotherapy after a partial surgical removal of a noncancerous meningioma had no recurrence after 10 years [10]. This outcome is similar to that of people who have complete removal of a noncancerous meningioma.
Stereotactic radiosurgery — Stereotactic radiosurgery is an alternative to external beam radiation therapy. This does not actually involve performing surgery, but instead uses narrow beams of radiation that are delivered from multiple angles. This allows a very high dose of radiation to be delivered to a narrow area. This approach may offer substantial advantages to a person with a meningioma because it is able to deliver more radiation to the tumor while minimizing the amount of normal brain that is affected. In contrast to conventional external beam radiation therapy, stereotactic radiosurgery is given as a single treatment.
Stereotactic radiosurgery has been used to deliver adjuvant radiation therapy following partial removal of a meningioma. It has also been used as an alternative to surgery for patients with relatively small meningiomas that cannot be completely removed with surgery. Stereotactic radiosurgery and surgical removal have similar long-term outcomes for patients with small meningiomas [11].
Stereotactic radiotherapy — Stereotactic radiotherapy is slightly different than stereotactic radiosurgery, although both use multiple narrow beams of radiation directed from different angles. However, stereotactic radiotherapy divides the dose into several treatments rather than giving the dose in one single treatment. The intent of stereotactic radiotherapy is to reduce radiation injury to nearby brain structures while maintaining tumor control.
This technique has been particularly useful in meningiomas of the optic nerve sheath, as well as those arising at the base of the skull.
Watchful waiting versus treatment — If a meningioma is small and does not cause symptoms, it may be possible to postpone surgery and/or radiation therapy. The decision to delay treatment is also influenced by the location and size of the tumor, as well as the person's overall medical condition. Treatment is usually considered if there is evidence of tumor growth or if the person develops symptoms.
Watchful waiting requires periodic physical examination along with an imaging test (MRI or CT scan of the head). This is usually recommended every three months for one year, then once per year, assuming that the meningioma does not grow or cause symptoms during this time.
Outcomes do not appear to be worse in patients who are closely monitored. In a review of 60 patients who were diagnosed with small, asymptomatic meningiomas, none developed symptoms during an average of 32 months [12]. Of the 45 patients who had a repeat MRI or CT, 35 had no increase in the size of their tumor, while the remaining 10 showed slow tumor growth, even over the course of up to 15 years.
Systemic therapy — Several treatments, including chemotherapy, hormone therapy, and immunotherapy, have been studied in patients whose tumor recurs after surgery and/or radiation therapy. These treatments are referred to as systemic treatments because they are given by mouth or into a vein and can affect the entire body. The goal of systemic therapy is to slow the growth of the meningioma. The benefits of systemic therapy are usually limited and the treatment is not intended to cure the condition. If possible, re-irradiation or repeat surgery should be considered.
Systemic treatments have been used for patients with malignant meningiomas in an attempt to prevent recurrence. Although initial reports were positive, subsequent studies have not confirmed a benefit. Thus, systemic therapy is usually reserved for treatment of meningiomas that recur after surgery or radiotherapy.
OUTCOMES — The long-term outcome of people with meningioma depends upon several factors. For patients who require treatment of symptomatic or large meningiomas, the outcome depends upon the completeness of surgery and the meningioma type (ie, benign, atypical, or malignant). It is important to remember that discussions of outcomes are based upon averages; these averages do not necessarily predict how long an individual patient will survive. Small meningiomas that cause no symptoms and do not require treatment do not usually shorten a person's life. Complete resection of the tumor is possible in about 80 percent of patients with benign meningiomas, approximately 70 to 80 percent of whom survive at least ten years without a recurrence. For patients whose tumors cannot be completely removed and those with cancerous tumors, the rate of recurrence is markedly increased. However, the use of radiation therapy after surgery has improved outcomes, and the risk of recurrence may be similar to patients whose tumor is completely resected. Cancerous (malignant) meningiomas are much more likely to recur, even after complete surgical removal. Recurrence rates are somewhat lower after removal of atypical meningiomas, although recurrence is more frequent than in people who have surgical removal of a benign meningioma. The benefit of postoperative radiation is controversial in these patients.
CLINICAL TRIALS — Progress in treating meningioma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are conducted in many countries around the world. 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 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. American Brain Tumor Association
(www.abta.org)
American Cancer Society
(www.cancer.org)
National Cancer Institute
(www.cancer.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
OncoLink
(www.oncolink.com/index.cfm)
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Claus, EB, Bondy, ML, Schildkraut, JM, et al. Epidemiology of intracranial meningioma. Neurosurgery 2005; 57:1088.
2. Palma, L, Celli, P, Franco, C, et al. Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 1997; 86:793.
3. Jhawar, BS, Fuchs, CS, Colditz, GA, Stampfer, MJ. Sex steroid hormone exposures and risk for meningioma. J Neurosurg 2003; 99:848.
4. Custer, BS, Koepsell, TD, Mueller, BA. The association between breast carcinoma and meningioma in women. Cancer 2002; 94:1626.
5. Nakamura, M, Roser, F, Michel, J, et al. The natural history of incidental meningiomas. Neurosurgery 2003; 53:62.
6. Lieu, AS, Howng, SL. Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors. Epilepsy Res 2000; 38:45.
7. Rosen, CL, Ammerman, JM, Sekhar, LN, Bank, WO. Outcome analysis of preoperative embolization in cranial base surgery. Acta Neurochir (Wien) 2002; 144:1157.
8. Stafford, SL, Perry, A, Suman, VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc 1998; 73:936.
9. Armstrong CL, Gyato K, Awadalla AW, Lustig, R, Tochner, ZA. A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev 2004; 14:65.
10. Goldsmith, BJ, Wara, WM, Wilson, CB, Larson, DA. Post-operative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994; 80:195.
11. Pollock, BE, Stafford, SL, Utter, A, et al. Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 2003; 55:1000.
12. Olivero, WC, Lister, JR, Elwood, PW. The natural history and growth rate of asymptomatic meningiomas: a review of 60 patients. J Neurosurg 1995; 83:222.
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:
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 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)
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:
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 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)
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:
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 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)
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:
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 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)
Learn How to Defend Your Dreams!
Learn How to Defend Your Dreams!
Have you ever been convinced to walk away from your dreams by people who manage to throw enough self doubt at you to win that war of attrition? The constant day in and day out negativity that pushes you to give up your dreams and conform to something you're not? "What are you nuts? You can't do that!" "Oh there's another hair brained scheme!" "Get Real! Go get a real job!" "Who do you think you are? You aren't something special, stick to the things you can handle." "What are you stupid or something? Why do you think you can do that?" "How on earth are you going to accomplish that?" Lambasting you with negativity, giving you the message "Who are you to become an author, or an inventor, or any number of other things your dreams may lead you to?" The litany goes on and on…
We are taught to focus on the impossibility of our dreams as adults, why things "can't be done"; to hide behind the "how" instead of understanding that the first step is to reconnect with our dreams in a magnificent flight of imagination. Don't worry about the "how" first; the means will come to you as part of the process. The question of "How are you going to do that?" is so often used as a weapon against us by negative people, proof of our "imminent failure." We are told to prematurely focus on the "how" before the "what" and this stops the process before it has even begun. The energy you generate by focusing on the what, will bring forth the how. Planning is a wonderful thing, there is nothing wrong with that, however if you focus on the fact that you "don't" know how yet, then you will miss all the possible "how's" that show up when you begin to truly entertain that dream first.
The fact of the matter is that we possess more personal power than we even know...I read a definition of personal power once that said that it is: "Your capacity to dream without limits and fulfill those dreams through your imagination." I'm afraid I do not recollect the author but I like the way they put it. The ability to manifest our own reality is the power of creation itself. I believe that developing these abilities is a gift to ourselves and the world.
It can be a long and sometimes difficult journey to re-discover those qualities in ourselves after years of being trained to deny their existence. We use our personal power as children without even knowing what we are doing but then we are trained what to believe, how to think, and to limit ourselves by having our perception and interpretation of the world dictated to us by our conditioning. As a child our personal power is limitless, but as we grow older it so often remains untapped.
So how do we overcome this onslaught of negativity that assaults our dreams, threatening to drown them out of existence? We must learn how to reinforce our mental immune systems. I call it "mental martial arts" ~ the ability to shatter belief systems that imprison the mind, body and spirit. We must earn our Black Belts as Dreamers!
So what is a Black Belt Dreamer? Why the concept of Mental Martial Arts and the term of "Black Belt Dreamer?" Because a Black Belt in martial arts is the highest rank of achievement in the skills of self-defense and mental discipline. In my newly published book "Becoming a Black Belt Dreamer ~ Unleash The Dream Warrior Within!" I have defined a focused, strong, step-by -process on how to stand your ground against the onslaught of daily negativity and nay-Sayers in your lives. This process utilizes martial arts philosophy and techniques, applying them to mental self defense, building up our mental immune system to fight to regain and protect that which is most precious; our ability to dream.
Perhaps it would help to give you a little history on the subject and what it means to me. In my life I have had to lean how to defend myself, not just physically, but mentally, emotionally and spiritually as well. As a child I grew up in a cult environment where I was constantly told I was worthless, useless and undeserving of love. I endured years of emotional and mental abuse. I grew up without knowing my biological father, watched helplessly as my mother was repeatedly robbed of her money and as my brother was exiled from the family at a young age. As devastating as this story sounds, it led me to one undeniable conclusion: I am a conqueror! At my lowest points in life (there's been more than one), a powerful and imaginative warrior was always there to rescue me. Now I know that warrior was me!
What started out as a passion for martial arts has expanded into far more than that, it became not just a means of learning physical self-defense and mental discipline, but also fueled my ability to defend myself spiritually and emotionally as well through the turmoil of a very restrictive and challenging upbringing. Why am I telling you this story? Because I strive to use my own experiences of oppression, abuse and isolation as real-life examples that every individual has the power to transcend any situation - no matter how hopeless it seems. That is how I became The Black Belt Dreamer - fighting, surviving and winning against all odds. I believe that regardless of our mistakes, traumas and tragedies, we all have an inner dream warrior that empowers us to walk through the fires o f life and create the reality we truly desire.
Listen to a message from Lyca Shan and find out more about: "Becoming a Black Belt Dreamer ~ Unleash the Dream Warrior within!" here: http://www.blackbeltdreamer.com/Newsletter/BBDNewsletter.html
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