Gliomas are a class of tumor that develops from glial (neuroepithelial or support) cells. Astrocytes, ependymal, and oligodendroglial cells are all examples of glial cells that compose the supportive tissue of the brain. Gliomas comprise nearly one-half of primary brain tumors and one-fifth of all primary spinal cord tumors. Contemporary classification of gliomas is based on the World Health Organization (WHO) system, which classifies the tumors according to the cell of origin and histologic features identified by the pathologist or neuropathologist. Low grade gliomas are slow growing, and are assigned either a I or II grade. From a practical standpoint, grade I tumors (such as the pilocytic astrocytoma) are usually excluded from conversation dealing with gliomas, as they constitute a distinctive pathologic and clinical entity. High grade (malignant) gliomas grow much more quickly, and are assigned either a III (anaplastic) or IV (glioblastoma multiforme) grade. Combined, grade III and IV gliomas represent about 40% of all primary brain tumors in patients aged 40-49 years, and 60% in patients older than 60 years. In most clinical series, grade III tumors comprise approximately 10% and grade IV 90% of the total number of high grade, malignant primary brain tumors.

Malignant gliomas are one of the most devastating tumors that can affect any given individual. Nevertheless, this past decade, major advances in the fields of molecular biology and cellular biology, as well as genomics, have begun to improve our current understanding of malignant gliomas. Grade IV gliomas, often referred to as Glioblastoma Multiforme or “GBM”, possess multiple genetic and chromosomal abnormalities which cause these tumors to grow rapidly. These tumors are unique in their capacity to proliferate uncontrollably and aggressively invade, infiltrate and destroy neighboring areas of the brain. However, it is very rare for such tumors to metastasize (spread) outside the central nervous system. As a GBM progresses, portions of the tumor often outgrow the immediate blood supply and die or “undergo necrosis”. In contrast, peripheral regions of the tumor readily recruit the growth of new blood vessels (angiogenesis), enabling continued rapid growth of the GBM. The aforementioned features of grade IV gliomas occur simultaneously within a given tumor cell population, resulting in a heterogeneous histologic and genetic mosaic pattern, hence, the term Glioblastoma.

What are the signs and symptoms of a glioma?

The presenting symptom(s) of a glioma depend on the location of the tumor within the brain and its rate of growth. Common symptoms include: headaches, seizures, difficulty speaking, weakness/paralysis in one part of the body or face, difficulty with vision, impairment of sensation, impairment of balance, nausea/vomiting, behavioral changes, and impairment of memory or thinking. The clinical course of an untreated malignant glioma is characterized by relentless invasive growth and, even with treatment, near universal recurrence.

How is a glioma diagnosed?

The majority of patients harboring a malignant glioma have had one or more of the aforementioned clinical symptoms of varying duration (usually weeks to months). Occasionally, a patient may present with no prior neurological symptoms. In this uncommon scenario, the glioma is discovered “incidentally” on a head CT scan performed on a patient for other reasons, such as an auto accident or a fall with associated head trauma.

In evaluating most brain tumors, magnetic resonance imaging (MRI) of the brain is usually preferred over a CT scan. MRI is better at establishing a presumptive diagnosis and delineating the suspected brain tumor in three planes, thereby allowing more exact localization of the tumor in relation to critical areas of the brain. Multi-voxel magnetic resonance spectroscopy (MRS) is now readily available at most medical centers. MRS is capable of characterizing the “chemical fingerprint” of a brain lesion non-invasively. Furthermore, positron emission tomography (PET) scanning can provide information about the metabolic potential of a brain lesion; a more intense signal suggests a greater reproductive potential, and in the case of a glioma, a more aggressive and faster-growing tumor.

Although these non-invasive diagnostic tests are helpful, the gold standard for accurate diagnosis of a glioma is a pathologic examination of tissue samples obtained from biopsy. The field of neuropathology is quickly being redefined by the use of highly specific immunologic and molecular markers. Such tests use special (histologic) stains that are linked to an antibody that specifically binds to a particular receptor on the surface of either normal cells or tumor cells. The receptors on the surface of the cell are controlled by a special code designated by a particular gene in the cell’s nucleus. An aberration in the gene controlling the blueprint of the cell’s surface receptor will produce a corresponding aberrancy on the surface receptor of the cell. The complex structure consisting of the special stain, the antibody and the cell surface receptor on the tumor cell form a so-called “tumor marker”. These markers can now be identified and characterized, facilitating the diagnosis of a malignant glioma, and eliminating the guesswork of traditional methods. Once a definitive diagnosis has been established, a customized treatment plan is developed for the individual patient, based on his or her unique circumstances.

What treatment options are available for malignant glioma?

Traditional treatment options for malignant gliomas include: surgery, radiation
therapy, and chemotherapy.

Surgery

Open surgery, through a window cut into the skull (craniotomy), is the primary form of treatment for malignant gliomas. The goal of surgery is to remove as much of the visible tumor as possible without damaging normal neurological functions. The invasive and infiltrating nature of malignant gliomas make this a very challenging task, despite recent advances in operative neurosurgery. Fortunately, an array of new technologies, such as operating microscopes, microdissection techniques, intraoperative computerized image-guidance, intraoperative ultrasound, intraoperative brain mapping, and most recently, real time MR imaging, makes surgical resection of gliomas safer than ever. Among patients with anaplastic astrocytoma and glioblastoma, there appears to be a definite increase in survival in those patients who have had at least a 97% or greater resection of their tumor, and in those patients whose tumor is located in the frontal lobe of the brain, as opposed to the temporal or parietal lobes.

Although not curative, aggressive removal of malignant glioma can immediately alleviate symptoms caused by the mass of a tumor and improve the effectiveness of other therapies; if not removed, the hypoxic/necrotic central portions of a tumor tend to be particularly resistant to radiation and chemotherapy. Furthermore, resection of a malignant glioma provides the neuropathologist with the best possible tissue sampling and permits an optimal histologic and genetic analysis of the tumor.

Radiation therapy and chemotherapy

Radiation therapy and chemotherapy are widely used as secondary or adjuvant treatments following surgery. Both therapies have a growth-suppressant effect on the tumor. Among patients who are not surgical candidates, either radiation or chemotherapy can be used as an initial treatment, but typically only after a biopsy has established the diagnosis of malignant glioma. Patients who are poor operative candidates generally include those who:

are medically unstable
have multiple active cancers simultaneously
have tumor spread to both brain hemispheres
have a glioma in an inoperable location (e.g. brain stem)
are opposed to surgery

A therapeutic role for postoperative radiation therapy was clearly established 25 years ago in a randomized trial carried out by the Brain Tumor Cooperative Group. In this study, the 14-week mean survival for patients undergoing surgery alone was extended to 42 weeks by the administration of daily (fractionated) radiation therapy delivered over a 6-week period of time. The typical total dose of conventional radiation therapy used to treat malignant gliomas is approximately 60 Gray (Gy). Such treatment is delivered to the tumor, plus a 2-3 cm margin surrounding the tumor, as determined on either a preoperative MRI or CT scan. The purpose of the additional margin of radiation is to compensate for less than perfect beam alignment and to treat the area of surrounding normal brain that is in the process of being infiltrated with tumor cells that are not visible by either MR or CT imaging.

With conventional radiation therapy, the daily dose is intentionally kept low and the technique of delivery is designed to maintain a uniform intensity of radiation, i.e. dose homogeneity. This latter concept ensures that no area of the tumor or surrounding normal brain receives too large or small a dose of radiation. Unfortunately, substantial regions of normal-functioning brain can be injured by the significant margin included in the radiation field.

Typical modern radiation therapy uses a linear accelerator to fire beams of radiation at a tumor from several directions. Most contemporary methods of radiation therapy use computer-controlled beam shaping devices to better conform the target volume to the shape of the tumor being treated. The best of these techniques, termed Intensity Modulated Radiation Therapy (IMRT), uses a computer to vary the intensity and shape of each radiation beam. The net benefit of IMRT is to better conform the dose of radiation to the tumor, even when the lesion has a very complex shape.

Complications of Radiation Therapy

With conventional daily-fractionated radiation therapy, the common short-term side-effects (which occur in days to weeks) are fatigue, loss of appetite and nausea. Skin rashes and hair loss often also occur over substantial regions of scalp. Delayed side-effects (occurring within months to years) can include varying degrees of memory loss and impairment of reasoning or thinking. More rarely, patients can experience impairment of pituitary function or radiation necrosis (a collection of dead tumor cells and scar tissue). Radiation necrosis can produce symptoms that are often very similar to the initial tumor presentation and includes severe headache, motor weakness, visual problems, or seizures.

What is the role of stereotactic radiosurgery in the treatment of gliomas?

Inevitably, high grade glial tumors will recur (progress) despite aggressive surgical removal and even the best of radiation therapy. Recurrence will usually develop at the margins of previously resected and irradiated tumor in approximately 80% of the cases. After tumor recurrence, a large, single dose of radiation (radiosurgery) can sometimes be used to treat this area of tumor recurrence. Unlike conventional radiation therapy, which seeks simply to suppress the growth of the glioma, the goal of radiosurgery is to create a zone of tumor destruction. In addition, radiosurgery can occasionally be used to ablate glial tumors in patients who are otherwise not surgical candidates and patients who cannot tolerate daily radiation.

Although there are several types of devices used to administer radiosurgery, the principle of delivering a high dose of radiation to a precisely localized target is the same. Some technologies, like the Gamma Knife, use radioactive cobalt as a source of ionizing radiation. A linear accelerator produces the radiation in other devices. Regardless of the source of radiation, nearly all methods of radiosurgery use stereotactic frames that are anchored to the patient’s skull with invasive aluminum or titanium screws. The frame serves to accurately localize the tumor in space and immobilize the patient’s head. The CyberKnife is the only radiosurgery device that does not require such a frame for precise targeting. As a result, this instrument uniquely enables doctors treating gliomas to divide a large radiosurgical dose into more than one stage or fraction staged radiosurgery. Staged CyberKnife radiosurgery is of particular benefit to patients who have previously received large doses of conventional radiation therapy and patients with gliomas located near critical areas of the brain.

What are the advantages of CyberKnife radiosurgery for gliomas?

In addition to offering the benefits of staged treatment, CyberKnife radiosurgery also eliminates the pain and discomfort associated with attachment of the head frame used with other radiosurgery devices. With the CyberKnife, there are no incisions or puncture sites from screw placement, no potential for bleeding or infection, no pain, and no post-procedure recovery time. Furthermore, the unique robotic non-isocentric targeting system of the CyberKnife makes it possible to better conform a dose of radiation to the often irregular shape of malignant gliomas.

What can I expect following CyberKnife radiosurgery?

The modern surgical treatment of acoustic neuromas continues to deliver ever better patient outcomes. Standard microsurgical resection (open surgery using a microscope) is most advisable for very young patients or those with large tumors. Meanwhile, stereotactic radiosurgery is an important treatment alternative for almost all other patients with acoustic neuromas. The non-invasive approach embodied by CyberKnife radiosurgery holds the promise of even better rates of hearing and facial nerve preservation. Ongoing studies are in the process of substantiating such clinical results.

References

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