Posted on March 8th, 2009 by
Ted Kennedy’s Recent Diagnosis of Glioblastoma Raises Awareness of Brain Cancer
Understanding this complex disease and its treatment options
By Linda M. Liau, MD, PhD and Charles H. Weaver, MD
The recent diagnosis of Ted Kennedy with brain cancer has raised awareness of this disease which affects approximately 20,000 people in the United States each year,1 but individuals should be encouraged as they fight this illness; the treatment options available today are providing more hope than ever before.
No one will argue that brain cancer remains a very complex disease: more than 120 different types of brain tumors have been identified, making an accurate diagnosis challenging; most brain tumors are not associated with any known risk factors, so they cannot currently be prevented; treatments are often risky due to potential damage to normal brain tissue; and prognosis depends on a multitude of factors, including tumor location and tumor type as well as patient age and personal health status.
But despite these challenges, diagnostic techniques and surgical technologies have dramatically improved in recent years, and ongoing research is paving the way for new and better treatments. Patients have reason to remain hopeful.
To help you or your loved one through the experience of brain cancer, it is essential to be knowledgeable about brain tumors and understand the treatment options.
Brain Tumor Types
Choosing the most appropriate treatment for a brain tumor depends on having the correct diagnosis. In general, brain tumors can be classified according to two major categories: the first is primary brain tumors, which begin in the brain and rarely spread to other parts of the body; the second is metastatic brain tumors, which begin as cancer in another part of the body (such as lung, breast, colon, kidney, or skin2,3) and spread to the brain. Metastatic brain tumors are the most common type, accounting for 160,000 diagnoses each year in the United States.1
Brain Tumor Symptoms
Although symptoms vary depending on a tumor’s location, the most common brain tumor symptoms include the following4:
- Nausea or vomiting
- Seizures or convulsions
- Difficulty thinking, speaking, or finding words
- Personality changes
- Weakness or paralysis in one part or one side of the body
- Loss of balance
- Vision changes
- Confusion and disorientation
- Memory loss
Primary Brain Tumors
Primary brain tumors are classified by how the cells behave (from the least aggressive, or benign, to the most aggressive, or malignant) and by the type of cell from which the tumor originates.
Some tumor types are assigned a grade, which signifies the rate of growth. Grading is a determination of what stage, or how advanced, a tumor is in its development. The World Health Organization (WHO) classifies all cancers on a grade of I to IV, with a grade of I or II being slow growing and/or benign and III or IV being faster growing and/or malignant.5 Even though a brain tumor may be classified as benign, it still can be very dangerous if it is in a risky or inoperable location. The classification and the grade of a tumor help predict its behavior, but it is important to note that no two tumors are alike. Cellular makeup, speed of growth, location of tumor, and even the patient’s age and immune system-all can affect tumor behavior, resulting in a variety of symptoms and different experiences among patients.6,7,8,9,10
Types of primary brain tumors
The most common type of primary brain tumor is a glioma, which originates in the brain from glial cells. Glial cells are the support cells of the central nervous system (CNS), helping neurons and nerve cells do their jobs. There are many types of gliomas11:
- Astrocytoma. The tumor arises from star-shaped glial cells called astrocytes. Astrocytes are cells that normally play an important role in maintaining the blood-brain barrier-the filtering mechanism that protects the brain. These tumors begin, when for reasons not completely known, a single astrocyte becomes abnormal. If that abnormal astrocyte multiplies, it will produce other astrocytes, eventually forming an astrocytoma.
- Glioblastoma multiforme (GBM). This is the most malignant astrocytoma (grade IV) and is the most common malignant brain tumor in adults.11
- Oligodendroglioma. This tumor type arises from cells that make the fatty substance that covers and protects nerves. They can be low-grade (WHO grade II) or anaplastic (WHO grade III), often contain calcifications, and are most common in middle-aged adults.12
- Ependymoma. The tumor arises from cells that line the central canal of the spinal cord. They are most commonly found in children and young adults.13
Some types of primary brain tumors do not begin in glial cells. These are the most common:
- Meningioma. This tumor occurs in the meninges and usually is slow growing. Meningiomas are quite common, accounting for about 25 percent of primary brain tumors and the majority of spinal cord tumors. They are almost twice as common in women than in men.14
- Vestibular schwannoma. This tumor arises from Schwann cells, which line the nerve in the inner ear that controls balance and hearing. The tumor, also called anacoustic neuroma,occurs most often in adults.
- CNS lymphoma. Lymphomas in the brain may be primary or secondary. Both are pathologically identical, and the diagnosis depends on whether another source of the lymphoma can be found elsewhere in the body. These tumors are initially very responsive to steroids, which can help in the diagnosis.15,16
- Sellar region tumors. These tumors, which include pituitary adenomas and craniopharyngiomas, grow at the base of the brain, near the pituitary gland, and are often associated with hormonal problems.
- Pineal region tumors. These rare brain tumors occur in or near the pineal gland, which is located between the cerebrum and the cerebellum.17
- Colloid cysts.These tumors classically occur in the third ventricle (a fluid-filled space in the brain) and can cause blockage of cerebrospinal fluid (CSF) flow. They are slow-growing, benign tumors, but there is a risk of sudden death due to CSF obstruction.18
- Medulloblastoma. This tumor is the most common brain tumor in children, accounting for 15 to 20 percent of pediatric brain tumors. This type usually arises in the midline of the cerebellum.19
Diagnosing a Brain Tumor
A brain tumor diagnosis usually involves several steps, including a neurological examination, brain scan(s), and/or biopsy and surgical removal. It is very common for people diagnosed with a brain tumor to seek a second opinion.
- A neurological exam is a series of tests to measure the function of the patient’s nervous system and mental alertness. If responses are not normal, a doctor may order a brain scan.
- A brain scan is a picture of the internal structures in the brain. Some types of scans use a contrast agent (dye), which helps the doctor to see the difference between normal and abnormal brain tissue. There are four common scans:
- An MRI (magnetic resonance imaging) is a scanning device that uses magnetic fields and computers to capture images of the brain on film. It does not use X-rays yet provides pictures from various planes, enabling doctors to create a 3D image of the tumor. The MRI can provide clear images of most tumors. Some medical centers have intraoperative MRI scanners, which are used during surgery to help ensure accurate and successful surgical removal of brain tumors.20
- A CT scan (computerized axial tomography) combines sophisticated X-ray and computer technology to show a combination of soft tissue, bone, and blood vessels. CT images can determine some types of tumors as well as help detect swelling, bleeding, and bone and tissue calcification. CT scans involve exposure to ionizing radiation, so the risks and the benefits of such scans should be discussed with a doctor.
- A PET (positron emission tomography) scan provides a picture of the brain’s activity rather than its structure. Physicians use PET scans to see the difference between scar tissue, recurring tumor cells, and cells destroyed by radiation treatment.21
- Angiography allows doctors to view the blood supply of a tumor. This test is particularly useful before surgery to help the surgeon plan the operation for vascular tumors and meningiomas.
- A biopsy is a surgical procedure in which a sample of tissue is taken from the tumor site and examined under a microscope. The purpose of a biopsy is to discover the type and the grade of a tumor. Getting a tissue sample of the tumor is still the most accurate method of obtaining a diagnosis.
- An open biopsy is done during a craniotomy, which involves removing a piece of the skull to get access to the brain. After the tumor is removed or partially removed, the bone usually is put back into place.
- A closed biopsy (also called a stereotactic or needle biopsy) may be performed when the tumor is in an area of the brain that is difficult to reach. In a closed biopsy, the neurosurgeon drills a small hole into the skull and passes a narrow, hollow needle into the tumor to remove a sample of tissue.
Brain Tumor Treatment
Brain tumors can be challenging to treat, but many brain tumors can be successfully treated with one or more methods. In addition, new technology is enabling physicians to target tumors more precisely, and innovative treatments under investigation are offering hope for the future.
Deciding on an appropriate treatment regimen often requires the expertise of an entire medical team, as treatment depends on a number of factors, including the type, location, size, and grade of the tumor, as well as the overall health of the patient. It is important to work closely with your doctor so you feel comfortable with the treatment regimen recommended for you.
The first line of treatment for a brain tumor is usually surgery, with the goal to remove as much of the tumor as possible without destroying normal function. Some tumors, such as meningiomas, schwannomas, and low-grade gliomas, may be treated by surgical removal alone or by surgery combined with radiation therapy.22 Tumors such as glioblastomas cannot be treated by surgery alone because cells from the tumor get too far into the normal surrounding brain tissue.23 In cases where the tumor is large and causing significant pressure, removal of the tumor can reduce symptoms such as headache, nausea, vomiting, and blurred vision. Surgery also can prolong life even if all of the tumor cannot be removed.24
The most common type of surgery for diagnosis and treatment of brain tumors is a craniotomy, which involves the removal of a piece of the bone of the skull to access the tumor. There is growing data to suggest that more-complete surgical removal, whenever possible, is associated with a better prognosis.24,25
Surgical resection of a tumor is usually not recommended in the following cases:
- The tumor is too deep within the brain.
- The tumor is located in portions of the brain with important functions.
- The patient is unable to tolerate a major operation.
Sometimes shunts are placed to bypass a blockage of the flow of cerebrospinal fluid. Without this bypass, a blockage can cause the fluid to build up within the brain (a condition known as hydrocephalus), leading to a life-threatening increase in pressure on vital parts of the brain.26
Even after the most successful surgeries, residual microscopic tumor often remains, so additional treatment is needed to kill as many cells as possible. Radiation therapy uses high-energy X-rays or other types of ionizing radiation to stop cancer cells from dividing. It can be used when surgery is not advised, for tumors that cannot be completely removed, or after surgery to prevent or delay tumor recurrence.27
Radiation therapy can be delivered by internal or external means.
Internal or interstitial radiation therapy(brachytherapy) involves surgically implanting radioactive material directly inside the tumor.28,29
External beam radiationinvolves linear accelerators and cobalt machines that direct radiation at the tumor from outside the patient’s body. There are two main types of external beam radiation:
- Conventional radiation therapy delivers radiation to an entire region of the brain. The radiation is fractionated into many small doses and given over a period of time. Depending on the location and the size of the tumor, the treatment can either be focused, where X-rays are aimed at the tumor and area surrounding it, or involve whole-brain radiation therapy (WBRT), whereby radiation is aimed at the entire brain. WBRT is used to treat multiple tumors and metastatic brain tumors.30
- Stereotactic radiosurgery delivers a single high dose of radiation in a one-day session. With the aid of computer imaging, the location of the tumor is accurately calculated and radiation is delivered directly to the tumor.31,32
The most common side effects of radiation are fatigue, nausea, loss of appetite, and short-term memory loss. Most of these symptoms can be treated or, in some cases, will decrease or disappear after treatment has been completed. Skin reactions (such as rash, redness, or irritation) and hair loss may occur in the area where the radiation is focused.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body. Chemotherapy may be given alone or in combination with other treatments.
Treating brain tumors with systemic chemotherapy can be difficult because of the blood-brain barrier, which keeps out harmful substances such as bacteria and chemicals and can prevent some chemotherapy drugs from entering the brain. Researchers are currently testing drugs that may break through this barrier.33
Side effects of chemotherapy include hair loss, fatigue, mouth sores, easy bruising or bleeding, and lowered resistance to infection. Most side effects are temporary and go away after treatment is finished. If you have side effects, there are ways to ease their impact. For example, drugs can be given along with chemotherapy to prevent or reduce nausea and vomiting. Antibiotics can be given to prevent infection.
Some chemotherapy drugs can permanently damage certain organs and tissues such as the heart, kidneys, and nerves. These possible risks are carefully balanced against the benefits, and the health of these organs is carefully monitored during treatment. If serious organ damage occurs, the responsible drug is discontinued and replaced with another.
The most commonly used drugs are given orally, such as Temodar® (temozolomide)34,35 and CCNU (lomustine),36 or intravenously, such as BiCNU® (carmustine) and Camptosar® (CPT-11, (irinotecan).37
Another unique and effective way to deliver chemotherapy directly to brain tumors is through interstitial chemotherapy. With this method surgeons implant up to eight dime-sized Gliadel® Wafers-biodegradable wafers soaked with the chemotherapy drug BiCNU-directly into the brain after surgery. The chemotherapy wafers then release high concentrations of BiCNU locally over a period of two to three weeks; then they safely dissolve. Gliadel Wafers do not provide a cure for glioblastoma, but studies show that they may help keep some patients alive longer.38 The side effects associated with Gliadel Wafers are the same as those associated with surgery to remove the tumor. Current research focuses on combining these chemotherapy wafers with other therapies to increase their effectiveness.39 The wafers are also being studied for their merits in treating metastatic brain tumors,40 which affect thousands of women each year from solid tumor disease of the breast, lung, colon, kidney and skin.
Researchers are currently designing drugs that identify and attack brain tumors on the molecular level, with the goal of destroying cancer cells while preserving healthy ones. Monoclonal antibodies, for example, that are tagged with a toxin or radiation can be loaded into an implantable reservoir and then placed in a cavity created during surgery. In principle, these antibodies are intended to seek and specifically destroy the “foreign” tumor cells for which they were designed.41,42
Growth Factor Inhibitors
A large number of malignant brain tumor cells carry on their surface an abnormally increased number of certain growth factor receptors. Researchers are studying drugs that block these receptors that signal tumors to grow. Tarceva® (erlotinib) and Iressa® (gefitinib) are two such drugs that target the epidermal growth factor receptor (EGFR) and have been shown to shrink tumors in some patients.43
Angiogenesis inhibitors, a group of drugs under investigation for treating brain tumors, interfere with the growth of blood vessels. Because brain tumors cannot grow without blood vessels to provide them with nourishment, the goal of angiogenesis inhibitors is to starve tumors of the nutrients and the oxygen they need to grow.44 Avastin® (bevacizumab) is an angiogenesis inhibitor that is currently being used in combination with cytotoxic chemotherapy drugs to treat brain cancer.
Immunotherapy and Cancer Vaccines
Immunotherapy attempts to make the body’s own immune system more effective in finding and destroying cancer cells.45,46 Different techniques being studied to boost the immune system include cytokines (interferons and interleukins), which are created by the immune system and affect many different types of cells47; lymphocytes, which are cells that are able to fight cancer and can be grown in a laboratory and injected back into the tumor48; and tumor vaccines, which can be created from tumor cells that are removed, modified, and then transferred back to the patient.49,50
Another active area of research is the use of altered genes that will destroy tumor cells and shrink the size of a brain tumor while leaving healthy brain cells functional and unharmed. Usually, this genetic material is inserted into a virus and into liposomes, whose purpose is to serve as a delivery system. Clinical studies of gene therapy for brain tumors are still preliminary.51,52,53,54
Many patients are seeing the benefit of complementary medical treatment-which includes specialties devoted to nutrition, exercise, acupuncture, aromatherapy, massage therapy, meditation, and yoga-to help relieve symptoms, minimize side effects, ease pain, and generally improve quality of life.55
Tremendous advancements have taken place in the battle against primary brain tumors, and promising treatments are on the horizon. The best way to prepare for this journey is to empower yourself through knowledge.
For additional information about treatment options for brain tumors, please visit the following Web sites:
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- Nabhani T, Liau L. Neurosurgical and other treatment options for metastatic melanoma in the central nervous system: Part II. Contemporary Neurosurgery. 2005;27(13):1-6.
- Mahaley MS Jr, Mettlin C, Natarajan N, Laws ER Jr, Peace BB. National survey of patterns of care for brain tumor patients. Journal of Neurosurgery. 1989;71(6):826-36.
- Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica. 2007;114(2):97-109.
- Boudreau CR, Yang I, Liau LM. Gliomas: Advances in molecular analysis and characterization. Surgical Neurology. 2005;64(4):286-94; discussion 294.
- Freije WA, Castro-Vargas FE, Fang Z, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Research. 2004;64(18):6503-10.
- Khan-Farooqi HR, Prins RM, Liau LM. Tumor immunology, immunomics and targeted immunotherapy for central nervous system malignancies. Neurological Research. 2005;27(7):692-702.
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- Sehati N, Liau L. Adjuvant treatment for gliomas. Contemporary Neurosurgery. 2003;25(15):1-9.
- Jeuken JW, von Deimling A, Wesseling P. Molecular pathogenesis of oligodendroglial tumors. Journal of Neuro-oncology. 2004;70(2):161-81.
- Merchant TE, Fouladi M. Ependymoma: New therapeutic approaches including radiation and chemotherapy. Journal of Neuro-oncology. 2005;75(3):287-99.
- Perry A, Gutmann DH, Reifenberger G. Molecular pathogenesis of meningiomas. Journal of Neuro-oncology. 2004;70(2):183-202.
- DeAngelis LM. Primary CNS lymphoma: Treatment with combined chemotherapy and radiotherapy. Journal of Neuro-oncology. 1999;43(3):249-57.
- Gleissner B, Chamberlain M. Treatment of CNS dissemination in systemic lymphoma. Journal of Neuro-oncology. 2007;84(1):107-17.
- Bruce JN, Ogden AT. Surgical strategies for treating patients with pineal region tumors. Journal of Neuro-oncology. 2004;69(1-3):221-36.
- Bergsneider M. Complete microsurgical resection of colloid cysts with a dual-port endoscopic technique. Neurosurgery. 2007;60(2 Suppl 1):S33-S43.
- Lelievre V, Seksenyan A, Nobuta H, et al. Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Developmental Biology. 2008;313(1):359-70.
- Bergsneider M, Sehati N, Villablanca P, McArthur DL, Becker DP, Liau LM. Mahaley Clinical Research Award: Extent of glioma resection using low-field (0.2 T) versus high-field (1.5 T) intraoperative MRI and image-guided frameless neuronavigation. Clinical Neurosurgery. 2005;52:389-99.
- Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET: Comparison with 18F-FDG. Journal of Nuclear Medicine. 2005;46(6):945-52.
- Jeremic B, Bamberg M. Radiation therapy for incompletely resected supratentorial low-grade glioma in adults. Journal of Neuro-oncology. 2001;55(2):101-12.
- Silbergeld DL, Chicoine MR. Isolation and characterization of human malignant glioma cells from histologically normal brain. Journal of Neurosurgery. 1997;86(3):525-31.
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- Berger M. Role of surgery in diagnosis and management. In Apuzzo M, ed. Benign Cerebral Glioma. Park Ridge, Ill: American Association of Neurological Surgeons; 1995:293-307.
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- Vick NA, Paleologos NA. External beam radiotherapy: Hard facts and painful realities. Journal of Neuro-oncology. 1995;24(1):93-95.
- McDermott MW, Berger MS, Kunwar S, Parsa AT, Sneed PK, Larson DA. Stereotactic radiosurgery and interstitial brachytherapy for glial neoplasms. Journal of Neuro-oncology. 2004;69(1-3):83-100.
- Vitaz TW, Warnke PC, Tabar V, Gutin PH. Brachytherapy for brain tumors. Journal of Neuro-oncology. 2005;73(1):71-86.
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- Warnick RE, Darakchiev BJ, Breneman JC. Stereotactic radiosurgery for patients with solid brain metastases: Current status. Journal of Neuro-oncology. 2004;69(1-3):125-37.
- Hall WA, Doolittle ND, Daman M, et al. Osmotic blood-brain barrier disruption chemotherapy for diffuse pontine gliomas. Journal of Neuro-oncology. 2006;77(3):279-84.
- Pouratian N, Gasco J, Sherman JH, Shaffrey ME, Schiff D. Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. Journal of Neuro-oncology. 2007;82(3):281-88.
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine. 2005;352(10):987-96.
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- Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. Journal of Neuro-oncology. 2002;59(2):157-63.
- Lawson HC, Sampath P, Bohan E, et al. Interstitial chemotherapy for malignant gliomas: The Johns Hopkins experience. Journal of Neuro-oncology. 2007;83(1):61-70.
- Limentani SA, Asher A, Heafner M, Kim JW, Fraser R. A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. Journal of Neuro-oncology. 2005;72(3):241-44.
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- Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New England Journal of Medicine. 2005;353(19):2012-24.
- Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. Journal of Neuro-oncology. 2006;78(3):281-93.
- Prins RM, Liau LM. Immunology and immunotherapy in neurosurgical disease. Neurosurgery. 2003;53(1):144-52; discussion 152-3.
- Prins RM, Liau LM. Cellular immunity and immunotherapy of brain tumors. Frontiers in Bioscience. 2004;9:3124-36.
- Yang I, Kremen TJ, Giovannone AJ, et al. Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme. Journal of Neurosurgery. 2004;100(2):310-19.
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- Liau LM, Black KL, Martin NA, et al. Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report. Neurosurgical Focus. 2000;9(6):e8.
- Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clinical Cancer Research. 2005;11(15):5515-25.
- Rainov NG, Ren H. Clinical trials with retrovirus mediated gene therapy-what have we learned? Journal of Neuro-oncology. 2003;65(3):227-36.
- Shah AC, Benos D, Gillespie GY, Markert JM. Oncolytic viruses: Clinical applications as vectors for the treatment of malignant gliomas. Journal of Neuro-oncology. 2003;65(3):203-26.
- Vecil GG, Lang FF. Clinical trials of adenoviruses in brain tumors: A review of Ad-p53 and oncolytic adenoviruses. Journal of Neuro-oncology. 2003;65(3):237-46.
- Yoshida J, Mizuno M. Clinical gene therapy for brain tumors. Liposomal delivery of anticancer molecule to glioma. Journal of Neuro-oncology. 2003;65(3):261-67.
- Brain and Spinal Cord Tumors in Adults. American Cancer Society Web site. Available at:http://www.cancer.org/103.00/103.00.pdf. Accessed January 8, 2008.
- Brain Tumor Facts & Statistics. Brain Tumor Society Web site. Available at:http://www.tbts.org/itemDetail.asp?categoryID=384&itemID=16535. Accessed January 8, 2008.
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