Neurobase

The Problem

Brain tumors are a complex multiplicity of diseases that strike more than 100,000 Americans annually. The symptoms are debilitating, the cure rate in many types of tumors is very low, and the incidence is on the rise. Brain tumors cannot be prevented because their causes are still unknown.

Brain tumors are difficult to treat. Surgery and radiation therapy are effective but limited, due to the risk each places on the surrounding normal brain tissue. Chemotherapy has had only minimal success. A "good" surgical result can still leave the patient with severe physical incapacity. "Successful" radiation therapy to the brain can have deleterious long-term side effects.

Society in general and the medical community to a large degree are unaware of the magnitude of the brain tumor problem. Potential victims are unaware of risk factors, early symptoms warranting medical attention, and steps to take when symptoms develop. Doctors often do not consider the diagnosis of a brain tumor early enough in their work-up to proceed quickly to the appropriate diagnostic tests. The delay in diagnosis caused by both patient and doctor factors leads to a diagnosis frequently made when the disease is extensive, and treatment can be palliative at best, and oftentimes associated with the aforementioned high risk of disability. To make early diagnosis possible, public and professional education programs are necessary.

A solution to the brain tumor problem is just beginning to be approached in an organized fashion. Top scientists must continue to be attracted to this field. Research is underfunded, and more large scale capital must be directed toward the brain tumor effort. The physicians who care for brain tumor patients now realize the value of a multidisciplinary approach to this disease, and specialists are working together to develop new and effective forms of early diagnosis and therapy. With continued teamwork and commitment, the problem will be solved.

What is a Brain Tumor?
Brain tumors are abnormal growths of tissue found inside the skull. There are two categories of brain tumors:
·           A primary brain tumor is that which originates in the brain.
·           A metastatic (secondary) brain tumor occurs when cancer cells from other parts of the body - such as the lungs, kidneys, breasts and skin - spread to the brain.

Brain tumors are classified as either benign (noncancerous) or malignant (cancerous).

In most parts of the body, benign tumors are not particularly harmful. This is not necessarily true in the brain. Because the brain is housed within the rigid, bony confines of the skull, any abnormal growth can place pressure on sensitive tissues and impair functions. Also, any tumor located near vital brain structures can seriously threaten health.  A benign tumor growing next to an important blood vessel in the brain does not have to grow very large before it can block blood flow. Or, if a benign tumor is found deep inside the brain, surgery to remove it may be very risky because of the chances of damaging vital brain centers. On the other hand, a tumor located near the brain's surface can often be removed surgically.

A malignant tumor is life-threatening because it consists of cancer cells. A benign tumor may also be life threatening because of its location. In other words, a brain tumor composed of benign cells - but located in a vital area - is still considered life threatening.(2)

Tumor grade indicates the degree of malignancy.(3) Grade is based on the appearance of the tumor cells seen under the microscope. It is an attempt to predict the tumor's tendency to spread and its growth rate. This information can help doctors determine both the prognosis and how to treat a tumor.

An important difference between malignant brain tumors and malignant tumors originating elsewhere in the body lies with their potential to spread. Malignant tumors elsewhere in the body often spread (metastasize) to many sites including the brain. On the other hand, malignant brain tumors rarely spread outside the central nervous system
(CNS).

At present, brain tumors cannot be prevented because their causes are unknown.

1 Adapted with permission from the National Institute of Neurological Disorders and Stroke's guide Brain and Spinal Cord Tumors: Hope Through Research.
2 Adapted from the American Brain Tumor Association's A Primer of Brain Tumors: A Patient's Reference Manual.
3 Reprinted with permission from the American Brain Tumor Association's A Primer of Brain Tumors: A Patient's Reference Manual.
 

Brain Tumor Symptoms

Brain tumors may have a variety of symptoms ranging from headache to stroke. They are great mimics of other neurologic disorders. It is sometimes hard to know whether a CT Scan or MRI should be done if someone you know has some of the symptoms and signs noted below, but it is important to know that these studies will usually definitively establish whether a brain tumor is responsible for any of these symptoms.

The following symptoms immediately raise the question of a brain tumor:

     A new seizure in an adult.
     Gradual loss of movement or sensation in an arm or leg.
     Unsteadiness or imbalance, especially if it is associated with headache.
     Loss of vision in one or both eyes, especially if it is more peripheral vision loss.
     An eating disorder as a child.
     Double vision, especially if it is associated with headache.
     Hearing loss with or without dizziness.
     Speech difficulty of gradual onset.
 

The following symptoms are usually not the result of a brain tumor, but may sometimes be:

Headache is probably the most common symptom of a brain tumor. Most people with headache, even persistent or severe headaches, do not have a tumor.  However, some kinds of headache are particularly worrisome. A steady headache that is worse in the morning than the afternoon, a persistent headache that is associated with nausea or vomiting, or a headache accompanied by double vision, weakness, or numbness all suggest a possible tumor.  A change in behavior may also be caused by a brain tumor. The development of an "I don't care" attitude, memory loss, loss of concentration, and general confusion may all be subtle signs: here, an evaluation by a neurologist may be an important step, but a CT or MRI will also help. Infertility or amenorrhea (abnormal cessation of menstruation).  Some troubles which seem to be other diseases may in fact be a tumor: a stroke, even when it looks like one on a CT, may turn out to be the result of a tumor. Sometimes a fall can come from a seizure caused by a tumor. A pituitary tumor can present like a subarachnoid hemorrhage, a kind of stroke.
 

As you can see from this list, the possible ways a brain tumor can show up are quite varied. If you are concerned, you should call a doctor who is familiar with these tumors.  Early detection and treatment may increase survival - if symptoms persist, sometimes gentle urging for an MRI is important to assure that everything is all right.

By: Peter McL. Black, M.D., Ph.D.
Neurosurgeon-in-Chief
Brigham and Women's Hospital
and Children's Hospital
Boston, Massachusetts
 

How are Brain Tumors Diagnosed? (1)

Research has made major strides in the ability to detect and diagnose brain tumors. When a doctor suspects a brain tumor because of a patient's medical history and symptoms, he or she can turn to a number of specialized tests and techniques to confirm the diagnosis. However, the first test is often a traditional neurological exam.

Neurological Exam: A neurological exam checks eye movement; eye reflexes and pupil reactions; reflexes; hearing; sensation; movement; balance and coordination.

The next step in diagnosing brain tumors often involves special imaging techniques and laboratory tests that can detect the presence of a tumor and provide clues about its location and type. Special imaging techniques developed through research have dramatically improved the diagnosis of brain tumors in recent years.

The following is a brief description of the most commonly used techniques for diagnosing a brain tumor:

Computed Tomography (CT): CT uses a sophisticated X-ray machine and a computer to create a detailed picture of the body's tissues and structures. Often, doctors will inject an iodine dye into the patient before performing a CT scan. The dye, also called contrast material, makes it easier to see abnormal tissue. A CT scan often gives doctors a good idea of where the tumor is located and can sometimes help them determine the tumor's type. It can also help doctors detect swelling, bleeding and other associated conditions. In addition, CT scans can help doctors check the results of treatment and watch for tumor recurrence.

Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that can enable doctors to construct a three-dimensional image of the tumor. Contrast material is often injected as in CT.

Positron Emission Tomography (PET): PET provides a picture of brain activity rather than structure by measuring levels of injected glucose (sugar) or methionine (amino acid) that has been labelled with a radioactive tracer. Based on recent research, some scientists believe that PET scans offer important clues for diagnosis of brain tumors. For example, physicians sometimes have trouble detecting recurrent tumors with CT or MRI scans. Recent studies have shown that PET may make it easier to detect recurrent brain tumors. Scientists are also examining whether PET can help physicians tell the difference between benign and malignant tumors before performing a biopsy or surgery.  Similar results can be obtained with SPECT or functional MRI.

A final step in confirming the diagnosis of a brain tumor is a biopsy.

Biopsy: A biopsy is a surgical procedure in which a small sample of tissue is taken from the suspected tumor to determine an exact diagnosis. By examining the sample under a microscope, the pathologist - a physician who specializes in understanding how disease affects the body's tissues - can tell what kinds of cells are in the tumor.

1 Reprinted, in part, with permission from the National Institute of Neurological Disorders and Stroke's guide Brain and Spinal Cord Tumors: Hope Through Research.
 

Available Treatments

Surgery, radiation and chemotherapy are the three most commonly used treatments - individually or in combination - for brain tumors. In addition, research is rapidly introducing new treatment methods in the search for a cure.

Surgery
Surgery to remove or "debulk" as much tumor as possible is usually the first step in treating a brain tumor. When the residual or remaining tumor after surgery is as small as possible, further treatments are more effective. A surgically accessible tumor is one that can be removed without causing severe neurological damage. New technologies allow neurosurgeons access to tumors deep in the brain that were previously considered inaccessible. Some recently developed approaches include:

·           Techniques that allow for accurate tumor localization including stereotaxis and other image-guided systems. These enable minimally invasive surgery to identify the tumor and to leave normal brain tissue unharmed. In stereotaxis a computer uses information from CT or MRI to create a three-dimensional map of the operation site.  Intra-operative MRI (employed during actual time of tumor removal) will soon be available. It allows surgeons to operate on a patient inside the MR system, permitting "real-time" imaging of the operative field including a full 3-D image of an infiltrating tumor as it is removed.
·           A variety of new surgical tools are now widely used. Microsurgery enables neurosurgeons to look through a high-powered microscope to get a magnified view of the operating area. This makes it easier to see - and remove - tumor tissue while sparing surrounding healthy tissue. New instruments such as intra-operative MRI are allowing much more accurate resection. Ultrasonic aspirators use high frequency sound waves to vibrate tumors and break them up; an aspirator then "vacuums" the tumor fragments. Lasers (Light Amplification by Stimulated Emission of Radiation) release a beam of concentrated light energy that can destroy tissue. They are occasion-ally helpful for tasks traditionally performed with a scalpel. Surgeons can sometimes use a laser to remove an entire tumor, or can destroy remaining tumor tissue after surgery.
·           Collaborative efforts and better anatomic understandings allow removal of tumors from previously inoperable sites. For example, new approaches to skull-base surgery involve close collaboration among ear nose and throat (ENT) specialists, plastic surgeons and neurosurgeons.
·           Over the last few years there have been significant improvements in the use of evoked potential electrophysiological mapping of the brain's cortical surface. This technique allows doctors to use small electrodes to stimulate a nerve so its electrical response, or evoked potential, can be measured. By determining the role of specific nerves in a particular patient, surgeons are helped to avoid damage to sensitive areas of the brain. Surgery under local anesthesia with brain mapping techniques allows removal of tumors even from speech and motor areas and is well tolerated by patients.
·           Surgery in the future may be more widely used to deliver novel treatments such as gene therapy or certain chemotherapeutic agents as well as to resect tumors.

While not a recently developed technology, surgery for some patients may involve the insertion of a shunt into the brain when a tumor blocks the flow of cerebrospinal fluid and causes hydrocephalus. Shunts are flexible tubes used to reroute and drain fluid. Shunting of the fluid can relieve headaches, nausea and other symptoms caused by too much pressure inside the skull.

Adapted from "What's new in neurosurgery?" presentation at the Dana-Farber Cancer Institute by Peter McL. Black, M.D., March 4, 1996; and from "Recent advances" by Eben Alexander III, M.D., published in the second edition of Color Me Hope.

Radiation Therapy
Radiation therapy plays a central role in the treatment of most brain tumors whether benign or malignant. In most cases, surgery provides for initial diagnosis and removal of as much tumor as possible. Radiation therapy then targets the residual tumor with the goal of reducing its size or stabilizing it. For malignant lesions, even when it appears that all tumor has been removed, microscopic cells remain in the surrounding brain tissue. To prevent or delay recurrence, radiation therapy to treat these areas is recommended.  Some benign brain tumors may be life-threatening if their growth is not controlled; when the entire tumor cannot be removed safely, radiotherapy is often recommended postoperatively to prevent remaining tumor cells from growing. Other benign brain tumors are treated with radiation at time of recurrence.

·           Traditional Radiation Therapy. Traditional radiation therapy uses external beams of either x or gamma rays to destroy brain tumor cells. This therapy delivers radiation from outside the patient's body and usually begins a week or two after surgery, after the surgical incision heals, continuing with fairly uniformed dosages throughout the treated areas for approximately six weeks. Conventional therapy for brain metastases until recently involved whole brain radiation for a period of two weeks; however, effective new technologies are quickly replacing this method (see stereotactic radiosurgery).
·           Hyperfractionation. Hyperfractionation is essentially a modified version of traditional radiation therapy. This approach uses smaller, more frequent daily doses (fractions) of radiation for a specified length of time for tumors that do not respond well to standard radiation therapy. This allows for a higher overall daily dose; normal brain tissues seem to be spared to a greater extent.
·           Radiosensitizers. Many scientists are testing the usefulness of drugs known as radiosensitizers that make tumor tissue more vulnerable to radiation. For example, they are using the knowledge that hypoxic cells (low in oxygen) are particularly resistant to radiation, and that oxygen is a powerful radiosensitizer.
·           Stereotaxis, Stereotactic Procedures. "Stereo" in this context means three-dimensional in space; "tactic" refers to touch. A head frame, which is connected to a computer, is attached to the patient's skull; with the assistance of a CT or MRI scanner providing a three-dimensional image the frame helps pinpoint the tumor location without opening the skull. Recently the technology has been developed that replaces the head frame with navigational wands, robotic devices or other frameless systems, some of which locate the tumor by using skin-based markers to fix points in space. The recently developed cyberknife is used in conjunction with a frameless computerized guidance system.

Sometimes stereotaxis is used in conjunction with biopsy or surgery and helps the neurosurgeon in devising an approach to the tumor. During stereotactic radiosurgery, a single high dose of focal external beam radiation is delivered. Most of the time spent during the procedure is in precisely planning the delivery of radiation beams to focus on the tumor and minimize damage to surrounding, normal brain tissue. This is known as conformal treatment planning. Despite its name, stereotactic radiosurgery does not require a surgical incision, and in fact is a promising treatment option for patients who are not surgical candidates. In stereotactic radiotherapy, fractionated external beam radiation is delivered with multiple small doses.

While numerous technologies exist which vary in how they deliver radiation (Gamma Knife, LINAC and cyclotron) all share the goal of delivering high dose radiation while minimizing damage to surrounding tissue. The Gamma Knife uses multiple point sources of gamma radiation converging on one source. With the linear accelerator (LINAC), non-coplanar arcs are used. The cyclotron, which delivers high energy proton beams (positively charged atomic particles), is available in only two locations, Massachusetts and California.

Investigators using stereotactic radiosurgery have found that it can help them reach and treat some small (less than 4 cm) tumors located deep in the brain that were previously considered inoperable. Unlike traditional radiation therapy it can be repeated. It is increasingly considered to be the treatment of choice for multiple small metastatic brain tumors in persons whose cancer is otherwise stable. Occasionally the procedure is used for children and adults with small areas of residual tumor after surgery or as a boost after conventional radiotherapy.
·           Interstitial Brachytherapy. Radioactive "seeds" are implanted using stereotactic techniques directly into the tumor where they remain over a period of time; this allows them to target tumor cells which are in various stages of growth.
·           Boron Neutron Capture Therapy. During this procedure, a boron compound, which is picked up more selectively by tumor cells than by normal brain tissue, is given intravenously and is absorbed by the tumor. A single dose of radiation with thermal neutrons (produced by a cyclotron) is then administered which targets the boron in tumor cells. High-energy alpha particles are then released from the boron, travel a very short distance and are toxic to the tumor cells. While one U.S. clinical trial is currently underway, this treatment has not been widely adopted in this country.

Adapted from "Radiation," presented by Jay Loeffler, M.D. and Dennis Shrieve, M.D., Ph.D. at The Brain Tumor Society's New Frontiers Symposium, Boston, MA;
November 11, 1995.

Chemotherapy
Chemotherapy interferes with the normal function of the tumor, working so that it doesn't receive all the genetic information it needs to grow and either becomes sterile or cannot tolerate its environment. Because chemotherapies target cells that are dividing, they are especially toxic to malignant tissues. Some chemotherapeutic drugs can be taken orally at home, but some are injected into the bloodstream. Because not all tumors are vulnerable to the same anticancer drugs, doctors often use a combination of drugs for chemotherapy, and much chemotherapy research is seeking to determine the optimum combination of drugs that will effectively combat brain tumor growth.

Scientists are working to overcome a unique obstacle to effective chemotherapy for brain tumors - the blood-brain barrier, a network of blood vessels and cells that protect the brain and prevent certain molecules from passing through. A major challenge in brain tumor chemotherapy is to get the drugs where they need to be in the brain to do their job. Investigators are testing drugs that may open the barrier without worsening neurological deficits. Another experimental path aimed at improving drug delivery into the central nervous system is called interstitial chemotherapy. In this technique, doctors place disc-shaped wafers soaked with a biodegradable chemotherapeutic drug, BCNU, directly into the surgical cavity after a tumor is removed. This new technique may help physicians increase the dose of life-prolonging drugs while limiting side effects - since less of the drug spreads elsewhere in the body. Finally, intrathecal infusion, delivering chemotherapies directly into the spinal fluid, is employed to treat some brain, spinal cord and metastatic tumors.

In adults, oligodendrogliomas and CNS lymphomas often respond to chemotherapy. For persons who have brain metastases, the chemotherapy used in most treatment centers is that which has been found most effective with the primary cancer. In childhood brain tumors that spread outside the brain, for example to the bone and bone marrow, chemotherapy has played a major role. The most common example of this is childhood medulloblastoma. For children with this disease, chemotherapy is routinely used and in recent years it has remarkably decreased the incidence of spread outside the nervous system.

Chemotherapy has also found a place in the treatment of infants with brain tumors. These individuals are particularly susceptible to the harmful side effects of radiation therapy on the developing brain. Thus, chemotherapy has been used to delay the time to starting radiation, and in a few rare instances has even been able to replace radiation therapy.

Some treatment centers are combining high dose chemotherapy with autologous bone marrow transplantation. Chemotherapy is rarely used with benign brain tumors with the exception of some recurrent meningiomas, which respond to anti-progesterone agents.

Summarized in part from a series of talks given for the Houston Area Brain Tumor Support Group by Victor Levin, M.D.

Other Therapies

These treatments target the biological processes that cause a normal cell to become a cancer cell and then to multiply. They are most often used following standard treatments with tumors that have not responded to such treatments.

·           Angiogenesis Inhibitors are a class of drugs which interfere with the growth of tumor-associated blood vessels, effectively starving tumors of vital nutrients and oxygen.  The strategy which targets the tumor's blood supply is known in some treatment centers as angiostatic therapy. Anti-angiogenesis agents currently or soon to be under investigation include thalidomide, TNP-470, platelet factor 4 (PF4), interferon and angiostatin.
·           Differentiating Agents are a class of drugs which can convert immature dividing tumor cells into mature cells, stopping tumor growth. Examples include retinoic acid, phenylacetate, and bryostatin.
·           Immunotherapy aims to make the immune system more effective in seeking out and destroying cancerous cells. Currently under investigation are several tools considered useful for boosting the immune system:
          Interferons, a family of natural proteins created by the immune system which are toxic to many tumor cells;

Lymphocytes, which have a particular ability to fight cancer. These can be harvested, grown and activated in the laboratory using cellular transfer techniques and injected directly back into the tumor to boost an immune response. The cells most commonly used for this purpose are called lymphokine-activated killer (LAK) cells. "Tumor vaccines" are created when tumor cells are removed from the patient and modified so that they can no longer grow when transferred back to the patient, but can elicit a powerful immunologic response against the tumor.

Gene Therapy involves the transfer of genetic material into a tumor cell to destroy the cell or to stop cell growth. Numerous types of genes are under investigation, including those that signal tumor cells to self-destruct, genes that make cells more mature (halting cell growth), genes that can strengthen the immune system's attack on the tumor, and those that increase the cell's responsiveness to certain drugs. Viruses are nature's own method for getting foreign genetic material into cells. By modifying a particular virus both to prevent a viral infection (by altering the virus so it won't divide) and to deliver a therapeutic gene to the tumor, tumor cells are selectively damaged. Gene therapy viruses or "vectors" can be administered by way of a stereotactic injection directly into the tumor. This experimental treatment is currently   available only to those patients who have malignant brain tumors which have not responded to standard chemotherapy.

Derived from "Biological Therapies," presented by Howard Fine, M.D. at The Brain Tumor Society's New Frontiers Symposium, Boston, MA; November 11, 1995.

This information was developed by the Brain Tumor Society and is herewith used with permission.

Brain Tumor Society. Basic Information About Brain Tumors. Available at: http://www.tbts.org/biabt.htm. Accessed November 19, 1999.

The information in this document is for general educational purposes only. It is not intended to substitute for personalized professional advice. Although the information was obtained from sources believed to be reliable, Arbor Publishing Corp, its representatives, and the providers of the information do not guarantee its accuracy and disclaim responsibility for adverse consequences resulting from its use. For further information, consult a physician and the organization referred to herein.

 Top of Page
 Top of Article