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There are many classification schemes for brain tumors, however a convenient start is to divide them into two main groups. The first group – PRIMARY BRAIN TUMORS - includes tumors which come from the tissues of the brain, or its’ immediate surroundings. The second group – METASTATIC BRAIN TUMORS - includes tumors which arise elsewhere in the body (such as the breast or lung) and migrate to the brain, usually through the bloodstream. Primary tumors may be benign or malignant. Metastatic tumors are, by definition, cancers (malignancies).
Common benign primary tumors include those originating from the lining of the skull - also called the meninges (meningiomas), nerves (schwannomas) and pituitary gland (pituitary adenomas). Even these tumors may occasionally become malignant. Furthermore, unless treatment results in nearly every tumor cell being destroyed or removed, even benign tumors can recur.
New surgical and radiation techniques can minimize the risk and discomfort of surgery, and may allow the patient to avoid or defer surgery with outcomes similar to those expected from a more traditional surgical approach.
With few exceptions, most tumors that arise from brain tissue (gliomas) are now considered to be malignancies ranging from relatively slow growing, invasive tumors (low grade) to rapidly growing and highly destructive tumors (high grade) such as glioblastomas. In the past, many practitioners referred to the low-grade tumors as being benign. It is now widely recognized that even low grade tumors are rarely cured and may evolve into higher grade tumors over time. Although the overall outlook for patients with these tumors has not changed radically since the 1960s, selected treatments improve the quality of life and have been shown to benefit certain patients. A variety of promising experimental approaches may lead to better treatments in the near future.
Metastatic tumors to the brain affect nearly one in four patients with cancer. Traditionally, the outcome for patients with these tumors was bleak, with the typical survival being only several weeks. More aggressive surgical and innovative radiation approaches can now lead to better quality survival, that is measured in months to years.
Brain tumors in children typically come from different tissues than those affecting adults. Also, treatments that are fairly well tolerated by the adult brain (like radiation therapy) may prevent normal development of a child’s brain. Common pediatric tumors include tumors of primitive cells that have not matured into adult cell types (primitive neuroectodermal tumors -- PNETs), tumors of the lining of the brain’s fluid sacs, also called “ventricles” (ependymomas) and benign tumors of the supporting cells of the brain (juvenile astrocytomas), as well as other gliomas.
It is thought that brain tumors arise when certain genes on the chromosomes of a cell are damaged so that they no longer function properly. These genes normally regulate the rate at which the cell divides (or if it divides at all), repair genes that fix defects of other genes, and genes that should cause the cell to self-destruct should the damage go beyond repair. In some cases, an individual may be born with partial defects in one or more of these genes. .Environmental factors may then lead to further damage. In other patients, the environmental injury to the genes may be the only cause. It is not known why some people in an “environment” develop brain tumors while others do not.
Once a cell is dividing too rapidly and internal mechanisms to check its growth are damaged, the cell can eventually grow into a tumor. Another line of defense may be the body’s immune system, which hopefully would detect the abnormal cell and kill it. Tumors may produce substances that block the immune system from recognizing the abnormal tumor cells and eventually overpower all internal and external checks to its growth.
A rapidly growing tumor may need more oxygen and nutrients than can be provided by the local blood supply intended for normal tissue. Tumors can produce substances which promote the growth of blood vessels, called “ angiogenesis factors.” The new vessels that grow increase the supply of nutrients to the tumor, and eventually the tumor becomes dependent on these new vessels.
Research is being done in these areas, but more research is needed.
Brain tumors (whether primary or metastatic, benign or malignant) are usually treated with surgery, radiation, and/or chemotherapy – alone or in various combinations. While it is true that radiation and chemotherapy are more often used for malignant, residual or recurrent tumors, decisions as to what treatment to use are made on an individual basis for each patient and depend on a number of factors. It should also be appreciated that each type of therapy has risks associated with it.
SURGERY
It is generally accepted that complete or nearly complete surgical removal of a brain tumor is beneficial for a patient. The surgeon’s challenge is to remove as much tumor as possible - without injuring brain tissue important to the patient’s neurological function (such as the ability to speak, walk, use their hands, etc.). Traditionally, surgeons relied on a large skull opening (or “ craniotomy”) to insure that they could get to the tumor, and subtle differences in the appearance between the tumor and more normal tissue to guide their removal. “Exploratory surgery” was practiced years ago - and frequently associated with complications.
Another procedure that is commonly done, sometimes before a craniotomy, is called a “ stereotactic biopsy”. This is basically a smaller operation used to obtain tissue, so that a diagnosis can be made. Usually, a frame is attached to the patient’s head, a scan is obtained, then the patient is taken to the operating area where a small hole is drilled in the skull to allow access to the abnormal area. A small sample is obtained, for examination under the microscope.
In the early 1990s computerized devices called surgical navigation systems were first devised which eliminated the need for exploration. These systems assisted the surgeon with guidance, localization and orientation. This information reduced the risks and improved the extent of tumor removal. In many cases it allowed inoperable tumors to be operable at acceptable risk. Some of these systems can also be used to do a biopsy procedure, like the one described above, without having to attach a frame to the skull. One limitation of these systems is that they use a scan (CT or MRI) obtained prior to surgery to guide the surgeon. Thus, they cannot account for movements of the brain that may occur intraoperatively. Investigators are developing techniques using ultrasound, and even doing surgery in MRI scanners, to help update the navigation system data during surgery.
Another type of surgery – called the placement of a “ ventriculo-peritoneal shunt” may be required for some patients with brain tumors. Everyone has spinal fluid within the brain (and spine) that is slowly circulating or flowing all the time. If this flow becomes blocked, the sacs that contain the fluid – or “ventricles” – can start to enlarge, creating increased pressure within the head. This is called hydrocephalus. If left untreated, hydrocephalus can cause brain damage and death. The neurosurgeon may decide to use a shunt to divert the spinal fluid, and therefore reduce the pressure. Usually, the shunt runs from the head - under the skin - down to the abdomen, where the fluid is allowed to drain into the abdominal (or “peritoneal” cavity). The shunt is usually permanent. If it becomes blocked, the symptoms are similar to that of the original condition of hydrocephalus – and may include headaches, vomiting, visual problems, and/or confusion or lethargy among others.
RADIATION
The goal of radiation treatments is to selectively kill tumor cells while leaving normal brain tissue unharmed. This may be accomplished in two ways. In standard external beam radiation therapy, multiple treatments of standard-dose “fractions” of radiation are applied to the brain. Each treatment induces damage to both healthy and normal tissue. By the time the next treatment is given, most of the normal cells have repaired the damage while the tumor tissue has not. This process is repeated for a total of 10 to 30 treatments (depending on the type of tumor). Ideally, 98 per cent of the tumor is killed and 98 per cent of the normal tissue survives.
The second way to selectively kill tumor cells is to focus an intense dose of radiation at the tumor from many points around the head. This process is called radiosurgery and uses special computers and delivery devices to accomplish the radiation treatment. Just as a magnifying glass can be used to focus sunlight to a point of intense heat while the rest of the area under the glass remains cool, these devices deliver highly focused doses of radiation to the target area of the tumor. Radiosurgery has been shown to be an effective treatment for many benign and malignant tumors. It has been used both as an alternative to, or combination with, conventional radiation and/or surgery.
Recently, treatments that take advantage of both of these principles of eliminating tumor while sparing normal tissue have been devised. “Stereotactic radiotherapy”, or “fractionated radiosurgery”, can be used to deliver multiple treatments of low dose radiation while matching the shape of the delivered radiation to the lesion. Theoretically, this should allow tumors to be safely and effectively treated, including tumors than are larger than those that can be managed with conventional radiosurgery.
CHEMOTHERAPY
In the past, exactly when to use chemotherapy to treat patients with brain tumors was somewhat controversial. This was because while it clearly had significant adverse effects, it was not always found to have a clear benefit. Today, however, chemotherapy is generally considered to be effective for certain pediatric tumors, lymphomas and some oligodendrogliomas. While it has also been proven that chemotherapy improves overall survival in patients with the most malignant primary brain tumors, it does so in only a fraction of the patients (about 20 per cent) and - so far -the patients who will benefit cannot be readily predicted before hand. As such, many patients (and their physicians) choose not to use chemotherapy because of the potential side effects (lung scarring, suppression of the immune system, nausea, etc.).
Chemotherapy also works by inflicting cell damage that is better repaired by normal tissue than tumor tissue. Resistance to chemotherapy might involve survival of tumor tissue that cannot respond to the drug, or the inability of the drug to past from the blood stream into the brain. A special barrier exists between the bloodstream and the brain tissue – the so-called blood-brain barrier. Some investigators have tried to improve the effect of chemotherapy by disrupting this barrier, or injecting the drug into the tumor or brain. The aim of another class of drugs is not to kill the tumor cells, but rather to block further tumor growth. In some cases, growth modifiers (such as Tamoxifen) have been used to attempt to stop the growth of tumors resistant to other treatments.
In 1996, a new method of delivering chemotherapy directly into the area of the tumor was approved by the U.S. Food and Drug Administration. This allows patients to receive chemotherapy without the systemic side effects. Chemotherapy-impregnated wafers can be applied by the surgeon at the time of surgery. The wafers slowly secrete the drug into the tumor.
INVESTIGATIONAL THERAPIES
Many types of new therapies are currently being studied, especially for types of tumors for which the prognosis is generally poor using the “conventional therapies” described above. It is not definitely known whether or not these therapies will work. Such therapies are given according to a “protocol”, and include various forms of immunotherapy, therapy with “targeted toxins, anti-angiogenesis therapy”, gene therapy and differentiation therapy. Combinations of treatments may also be able to improve the outlook for patients, while lowering the adverse side effects.
Perhaps the most appealing means of curing brain tumors would be to correct the underlying defects in the genes that led to tumor formation in the first place – so called “ gene therapy”. Theoretically, genes that promote growth could be turned off, those that suppress growth could be turned on, defective monitoring mechanisms could be turned on, genes that produce a beacon for the immune system could be delivered, and so on. This type of therapy has been used successfully in mice to rid them of primary and secondary tumors. Currently, the principal problem with gene therapy is that more malignant cells have to be reached or the tumor will quickly recur. Contemporary delivery systems (e.g. genetically engineered viruses) have been inefficient and unable to deliver enough to lead to tumor cure in actual patients. Nonetheless, gene therapy may well become an important future treatment for brain tumors, alone or in combination with the above therapies.
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