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A Review and Update: Gliomas by: Leonard J. Cerullo, M.D.
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Brain tumors account for nearly 1.4 % of all adult tumors, with gliomas being the most prevalent and accounting for 60% of brain tumors.(8) While neoplasms can arise from either the neuronal or glial components of the central nervous system, the glial tumors (gliomas) are by far more important both in terms of frequency and clinical aggressiveness. The most common gliomas are those derived from astrocytes and oligodendrocytes. These tumors vary in pathology, invasiveness, recurrence, and resistance to treatment. Even their treatments differ. More importantly, therapeutic options and outcomes vary among the types and grades of tumor. In this CINN Foundation Report, we will briefly discuss the key features of each tumor class, as well as current views on treatment options and new directions for future management, including advancements in molecular research.
Tumor Classification
The World Health Organization (WHO) has developed a classification scheme that rates (grades) gliomas from the least malignant to the most aggressive tumor type. The grading scale encompasses the various histopathological delineations and ranks them from Grades I thru IV (sometimes referred to as low vs. high grade). The most aggressive tumors have been assigned Grade IV or glioblastoma multiforme. The epidemiology of these tumors is extremely variable.
While it is extremely rare for primary brain tumors to metastasize, metastases to the brain are a common complication of other types of cancer occurring five to ten times more frequently than primary glial tumors.
Clinical Presentation
The clinical manifestation of various tumors can be appreciated in terms of tumor location, growth rate and size. There are three issues to consider in terms of symptomatology. First, tumor location plays a significant role in the focal neurological deficits exhibited by patients. For example, if the tumor is located in the frontal lobe, there may be motor, mood or personality changes. Similarly, tumors located in the dominant temporal region may be associated with speech or memory disturbances. Fast growing gliomas often produce increased intracranial pressure (ICP). Elevated ICP can be the result of obstructive hydrocephalus or edema, in addition to tumor burden and failure of cerebral compensatory mechanisms to accommodate the volume. In any event, the increased pressure will most likely result in complaints of headache, visual changes, vomiting, and nausea. Lastly, patients often present with seizures, especially in the case of oligodendroglioma. Again, the anatomical location of the mass would determine the type of seizure (e.g., motor with frontotemporal tumors and visual with occipital). In many instances, tumors are discovered incidentally by cranial imaging studies when a patient is seeking treatment for an unrelated health issue or following a head injury. This more likely occurs in benign, slow growing tumors.
Diagnostic and Treatment Options
Stereotactic Biopsy(9)
After imaging studies confirm the presence of an abnormality, the first step in the treatment of any glioma is the determination of the tumor’s cell type and grade of malignancy. It is not generally accepted practice to use results from imaging alone to diagnose a glioma, unless the location is such that a stereotactic biopsy or open biopsy would run an unacceptable risk of neurological complication. A biopsy should be obtained at the time of surgical intervention. If resection is not possible, a stereotactic biopsy should be performed in most cases. The stereotactic biopsy utilizes imaging and computer technology to access the lesion through “silent” areas of the brain through a burr hole. The obvious advantage is that the procedure is minimally invasive, thus reducing surgically related complications as well as recovery time. The procedure can be performed under local or general anesthesia. Following placement of the stereotactic headframe, the patient’s brain is imaged by Computed Tomography (CT), or Magnetic Resonance Imaging (MRI) scan, or a combination of the two. The entry point and target coordinates are then defined. A small burr hole is used to access the surface of the brain. The stereotactic probe is inserted using the coordinates determined by computer analysis beforehand. Obviously, the tissue sample is limited. As with any surgical procedure, there are limitations and risks to stereotactic biopsy. If the tumor is particularly solid, the probe may displace it. The surrounding tissue, rather than the tumor, will be sampled. There also is the possibility of a sampling error. Since this is a blind procedure, there is potential for damage to minor or major blood vessels depending on the location. Intracranial hemorrhage occurs in 1 – 3% of cases and may require open surgical treatment or result in significant neurological deficits. Furthermore, some targets may not be accessible with this technique.
Surgical Resection
Surgical resection is typically the first line of therapy in the treatment of gliomas. Resection is generally followed by adjuvant therapies described below. The goal of surgery is to maximally debulk the lesion and establish a tissue diagnosis. “Gross total resection” may be possible in lower grade lesions. True “gross total resection” is rarely possible with higher grade gliomas. There is debate on the value of extent of surgical resection of high grade gliomas. Some studies have indicated that if greater than 95% of the tumor can be surgically removed, there may be enhanced survival in high grade lesions. This, of course, selects fairly well demarcated lesions in non-eloquent areas of the brain. Therefore, this methodology does produce a selection bias. New technology, including Image Guidance and Neurophysiologic Monitoring, is allowing surgeons to more safely optimize resection. Awake craniotomy is occasionally indicated when resecting tumor in or near “eloquent” brain. Awake craniotomies have been utilized in the surgical treatment of epilepsy for decades. More recently, this technique has been selectively utilized in conjunction with cortical stimulation to allow for better outcome and better quality of life. Intraoperative diagnostic ultrasound can help compensate for brain shift when using image guidance. Intraoperative MR is being investigated in terms of cost/benefit in allowing a more complete intraoperatively verified resection.
Radiation Options
Following surgery, radiation therapy is recommended for higher grade lesions. This may either be conventional fractionated radiation therapy with a significant margin around the resected tumor bed (perhaps determined by FLAIR sequence MR), or intensity modulated radiation therapy (IMRT).iv IMRT allows for a more homogeneous field coverage of a complex geometric shape. Both are performed over several daily sessions. Hyperfractionated irradiation is the use of two or more treatments per day with fraction doses lower than conventional dosages. In theory, this enables the radiation oncologist to deliver a higher dose in the same overall treatment time. Following the completion of conventional or IMRT treatment, a boost to the tumor bed may be given using focused ionizing radiation.ii Stereotactic radiosurgery is the highly precise delivery of ionizing radiation in a single session. The two major types of radiosurgery delivery systems are the “fixed source” (Leksell Gamma Knife®) and the movable source linear accelerator (LINAC) devices. LINAC systems are either modified from standard equipment or specifically designed for radiosurgery (CyberKnife®, Novalis®). Stereotactic radiosurgery may also be used in selective cases as an alternative to reoperation at a later date.i There are volume limitations to avoid excessive dosing of the previously treated brain. Similarly, the presence of significant brain edema may be a contraindication to the therapy.7
Brachytherapy is another focal radiation technique that involves the implantation of radiation seeds (typically radioactive iodine) at the tumor site at some time after conventional radiation therapy. A major disadvantage is that the procedure requires the re-opening of the craniotomy. In addition, the radiation dose is less conformal than stereotactic radiosurgery and may produce significant necrosis. With the advent of stereotactic radiosurgery, most surgeons have opted to use brachytherapy less frequently or abandoned it completely.
Despite aggressive therapies and in even the face of improved surgical resection techniques, the statistical success in the treatment of high grade gliomas remains dismal. Clearly, new approaches to genetic modeling may offer more specific therapies designed for an individual neoplasm. Good prognostic indices include younger age of patient, higher Karnofsky scores, lower grade of tumor and extent of surgical resection. Patients with focal tumors do better than those with diffuse or multi-focal lesions. At the time of recurrence (which is usually at the site of the initial resection) a decision regarding salvage treatment may be made. Treatments include re-resection, stereotactic radiosurgery, and the use of implantable gene modifiers.
Chemotherapy
Systemic chemotherapy is often used to complement surgical resection and radiation for higher grade tumor. The most frequently used drugs are Temodor®, CCNU, and BCNU. The most promising drug today seems to be Temodar®.
A chemotherapy wafer impregnated with BCNU (Gliadel®) is being utilized in specific cases as a local chemotherapy treatment. The wafers are small dime-sized biopolymer wafers that deliver BCNU directly into the tumor cavity. At present, the wafers are being used at first resection (if appropriate) and at recurrence. The principal advantage of this technique is delivery of a higher concentration of BCNU. It is likely that other agents will be used via the same vehicle, which dissolves over two or three weeks releasing the agent at a constant rate into the tumor cavity and its immediate surrounding tissue.
Shortly, CINN will initiate a clinical research trial designed to investigate a technology to enhance the delivery of chemotherapy or targeted tumor therapy into recurrent glial tumors. Positive-pressure Convection-Enhanced Delivery (CED) infuses powerful anti-tumor agents (e.g., chemotherapy, gene therapy, immunotherapy) into the tumor cavity and extends them deeper into the peri-tumoral tissue. Early results are promising. CINN’s initial drug will be a highly specific tumoral targeting agent (Recombinant hIL13-PE38QQR cytotoxin). Selection criteria for the study include patients who:
- have had previous cytoreductive surgery establishing the diagnosis of glioblastoma or biopsy surgery for GBM;
- have had previous cytoreductive surgery establishing the diagnosis of glioblastoma or biopsy surgery for GBM;
- have received external beam radiotherapy with 48 Gy tumor dose, completed 4 weeks prior to study entry;
- have clinical or radiographic evidence of recurrent or progressive supratentorial tumor less than 5cm in maximum diameter measured less than two weeks prior to study entry;
- gross total resection (i.e., 95% resection of the solid, contrast-enhancing tumor component) must be planned.
- The treatment time will extend from three to five days.
Genetic Research
Results from several studies indicate that tumors within the same histological class are quite heterogeneous from a molecular genetic perspective.(10) By identifying key molecular markers, it may be possible to provide targets for tumor treatment. Several researchers have demonstrated that the mutation of the tumor suppressor gene, p53, is indicative of tumor formation in astrocytic tumors. Loss of p53 wild-type activity in cancer cells has been considered to be a major predictive factor in the failure to respond to chemotherapy11.
Given that some tumors express molecular mutations that are predictive of their sensitivity to various treatment strategies, these studies highlight the importance of developing therapeutic approaches that will be applicable to tumors with a range of genetic alterations. Ultimately, these data may provide the foundation upon which to develop new and more tumor specific drug therapies. We have ongoing research investigating the use of chemo-immuno-gene therapy combined with novel molecular genetic therapy in hopes of creating another mechanism of treatment for this otherwise fatal disease.
Alternative Therapeutic Options
Complementary and alternative medicine (CAM), as defined by National Center for Complementary and Alternative Medicine (NCCAM), a component of the National Institutes of Health, is a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine. While some scientific evidence exists regarding some CAM therapies, for most there are key questions that are yet to be answered through well-designed scientific studies—questions such as whether they are safe and whether they work for the diseases or medical conditions for which they are used.
By definition, complementary medicine is used together with conventional medicine. An example of a complementary therapy is using aromatherapy to help lessen a patient’s discomfort following surgery. Conversely, alternative medicine is used in place of conventional medicine. An example of an alternative therapy is using a special diet to treat cancer in lieu of undergoing surgery, radiation, or chemotherapy that would normally be the prescribed course of treatment. Examples of alternative medical systems that have developed in Western cultures include homeopathic medicine and naturopathic medicine. Examples of systems that have developed in non-Western cultures include traditional Chinese medicine and Ayurveda, which has been practiced primarily in the Indian subcontinent for 5,000 years.
Mind-body medicine uses a variety of techniques designed to enhance the mind’s capacity to affect bodily function and symptoms. Some techniques that were considered CAM in the past have become mainstream (for example, patient support groups and cognitive-behavioral therapy). Other mind-body techniques are still considered CAM, including meditation, prayer, mental healing, and therapies that use creative outlets such as art, music, or dance.
Conclusions
Malignant gliomas continue to be among the most lethal of human cancers. In some instances there are still more questions than answers. However, technological progress continues to provide insight and hope for increased therapeutic outcomes. Moreover, there are therapies (namely chemo-immuno-gene therapy) with tremendous potential as a protective therapy against recurrence. Perhaps another future direction is to begin by stratifying patients according to their genetic diagnosis, and design therapeutic modalities aimed at preventing malignant progression. Although at the present time, no molecular system for the classification of brain tumors has been generally accepted, there are many unfolding technologies that offer the exciting prospect of practical molecular classification in the future.
1. Chang, S.D., and Gibbs, I.C. : Stereotactic radiosurgery of gliomas. Contemporary Neurosurgery, 25 (19), September, 30, 2003.
2. Curran, Jr., Scott, C.B, and Leibel, S.A.: Issues in the Use of Conventional and Altered Fractionation Radiation Therapy for Pediatric and Adult Gliomas. In: Berger M.S. and Wilson, C.B. (Eds): The Gliomas. Philadelphia, PA, W.B. Saunders Company 1999, pp 480 – 488
3. Gonzales, M.: Classification and pathogenesis of brain tumors. In: Kaye A.H., and Laws Jr., E.R. (Eds): Brain Tumors. Philadelphia, PA, Churchill Livingston. 1997 pp31 -45
4. Larson, D.A., Shrieve, D.C. and Gutin, P.H.: Radiosurgery. .In: Berger M.S. and Wilson, C.B. (Eds): The Gliomas. Philadelphia, PA, W.B. Saunders Company 1999, pp 511- 526
5. Louis, D.N. and Cavenne, W.K.: Neoplasms of the Central Nervous System, In: DeVita VT Jr, Hellman S, Rosenberg SA, (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, Williams, & Wilkens. 2001, pp 2091- 2160
6. Perry, J.R., Louis D.N., and Cairncross, J.G.: Current treatment of oligodendrogliomas. Arch Neurol, 56, 434-436 April 1999
7. Pollock, B.E.: Management of complications from radiosurgery. Contemporary Neurosurgery, 25 (18), September, 15, 2003.
8. Sehati, N. and Liau, L.M.: Adjuvant treatment for gliomas. Contemporary Neurosurgery, 25 (15), July 31, 2003.
9. Spiegelmann, R. and Friedman, W.: Closed Biopsy Techniques. In: Berger M.S. and Wilson, C.B. (Eds): The Gliomas. Philadelphia, PA, W.B. Saunders Company 1999, pp376-390
10. Takeshima, H., Sawamura, Y., Gilbert, M.R., and Van Meir, E.G.: Application of advances in molecular biology to the treatment of brain tumors. Curr Oncol Rep., 2000, Sep; 2(5): 425-433.
11. Weller, M., Rieger, J., Grimmel, C., Van Meir, E.G., De Tribolet, N., et al.: Predicting chemoresistances in human malignant gliomas cells: The role of molecular genetic analyses. Int. J. Cancel (Pred. Oncol.): 79, 640-644, 1998
12. Wellons, III, J.C., Reddy, A.T., Tubbs, R., and Oakes, W.J.: Update on the treatment of intracerebellar pilocytic astrocytomas. Contemporary Neurosurgery, 25 (9), May 15, 2003
13. Wen, P.Y., Black, P.Mc., and Loeffler, J. S.: Treatment of Metastatic Cancer, In: DeVita VT Jr, Hellman S, Rosenberg SA, (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, Williams, & Wilkens. 2001, pp 2655-2669
14. Modified illustration from NCCN Practice Guidelines Version 1. 2001