AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. The current World Health Organization (WHO) classification of primary brain tumors lists GBM as a grade IV astrocytoma. It is highly malignant, infiltrates the brain extensively, and at times may become enormous before turning symptomatic.

Pathophysiology

GBM is an anaplastic, highly cellular tumor with poorly differentiated, round, or pleomorphic cells, occasional multinucleated cells, nuclear atypia, and anaplasia. Under the modified WHO classification, GBM differs from anaplastic astrocytomas (AA) by the presence of necrosis under the microscope. Variants of the tumor include gliosarcoma, multifocal GBM, or gliomatosis cerebri (in which the entire brain may be infiltrated with tumor cells). These variants, however, do not alter the prognosis of the tumor. Seldom do GBMs metastasize to the spinal cord or outside the nervous system.

Frequency

United States

Among primary brain tumors, malignant astrocytomas are the most common in all age groups. (However, among all brain tumors, metastases are the most common.) GBMs are the most common primary brain tumors in adults, accounting for 12-15% of intracranial tumors and 50-60% of primary brain tumors.

International

The incidence of GBM is fairly constant worldwide.

Mortality/Morbidity

Morbidity is from the tumor location, progression, and pressure effects. The overall prognosis for GBM has changed little in the past 2 decades, despite major improvements in neuroimaging, neurosurgery, radiation treatment techniques, and supportive care. Few patients with GBM survive longer than 3 years and only a handful survive 5 years. Previously reported long-term survivors of GBM may be patients diagnosed with GBM who actually harbor low-grade glioma, pleomorphic xanthoastrocytoma, ganglioglioma, or other lesions. Occasional patients with a single necrotic, demyelinating plaque of multiple sclerosis also may be misdiagnosed with GBM, especially if only CT scans are obtained.

Race

High-grade astrocytomas (HGAs) are slightly more common in whites than in blacks, Latinos, and Asians.

Sex

GBM is slightly more common in men than in women; the male-to-female ratio is 3:2.

Age

While GBM occurs in all age groups, its incidence is increasing in elderly patients. A true increase in incidence of primary brain tumors exists, which cannot be explained by the aging population, better imaging techniques, or earlier detection at surgery.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

GBM, like other brain tumors, produces symptoms by a combination of focal neurological deficits from compression and infiltration of the surrounding brain, vascular compromise, and raised intracranial pressure. Presenting features include the following:

• Headaches (30-50%)
• • Headaches are nonspecific and indistinguishable from tension headache.
  • As the tumor enlarges, it may have features of increased intracranial pressure.
• Seizures (30-60%): Depending on the tumor location, seizures may be simple partial, complex partial, or generalized.
• Focal neurological deficits (40-60%): As some patients with GBM survive longer, an increasing number of patients experience cognitive problems, neurological deficits resulting from radiation necrosis, communicating hydrocephalus, and occasionally cranial neuropathies and polyradiculopathies from leptomeningeal spread.
• Mental status changes (20-40%): With the advent of MRI, GBMs increasingly are diagnosed at an earlier stage and with subtle personality changes.

Physical

Physical findings depend on the location, size, and rate of growth of the tumor, as with any other CNS tumor. Tumors in less critical areas (eg, anterior frontal or temporal lobe) may present with subtle personality changes and memory problems. Similarly, motor weakness and sensory hemineglect are the hallmarks of tumors arising in the frontal or parietal lobes and thalamic regions. Sensory neglect is more prominent in right hemispheric lesions.

• Seizures are a common presentation of small tumors in the frontoparietal regions (simple motor or sensory partial seizure) and temporal lobe (simple or complex partial seizure).
• Occipital lobe tumors may present with visual field defects. Although these tumors are less frequent than tumors originating at other sites, patients generally are unaware of the slow onset of a cortically based hemianopsia.
• Brainstem GBMs are rare in adults. However, they may present with bilateral crossed neurological deficits (eg, weakness on one side with contralateral cranial nerve palsy). Alternatively, they may present with rapidly progressive headache or altered consciousness.

Causes

The etiology of GBM is unknown. However, at least two genetic pathways have been delineated in its development: de novo (primary) glioblastomas and secondary glioblastomas. De novo glioblastomas are most common. De novo GBM develops in older patients and demonstrates a high rate of epidermal growth factor receptor (EGFR) overexpression, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutations, and p16INK4A deletions. In contrast, secondary GBM develops in younger patients and develops from a malignant transformation of a previously diagnosed low-grade tumor. TP53 and retinoblastoma gene (RB) mutations are more common in the development of secondary glioblastomas.

Several genetic disorders are associated with increased incidence of gliomas (eg, tuberous sclerosis, neurofibromatosis types 1 and 2, Turcot syndrome, Li-Fraumeni syndrome). An association exists between ionizing radiation and astrocytomas. Children who receive low-dose intracranial radiation have a 2.6-fold increase in prevalence of astrocytomas, and prophylactic whole-brain radiation therapy in patients with acute lymphocytic leukemia increased the incidence of astrocytomas 22-fold. Other suspected risk factors, such as electromagnetic radiation and cellular telephone use, are yet to be substantiated by large epidemiologic studies.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Other brain tumors (eg, meningioma, metastasis, astrocytoma, oligodendroglioma)
Brain abscess
Large multiple sclerosis plaque
CNS toxoplasmosis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Routine laboratory workup results often are negative, but excluding a metabolic or infective process is important in an otherwise healthy patient who presents with new-onset seizures or mental status changes for the first time.

Imaging Studies

• The preferred workup is diagnostic neuroimaging studies; MRI with and without contrast is the most sensitive and specific study.
• • These tumors characteristically have low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images.
  • With contrast, the tumors usually enhance. The enhanced T1-weighted images typically have a central hypodensity surrounded by a thick enhancing rim of tumor.
• CT scan can be ordered with or without contrast when MRI is contraindicated or unavailable.
• • On CT scan, GBMs have a variable, inhomogeneous hypodense or isodense appearance with surrounding edema.
  • GBMs tend to infiltrate along the white matter tracts and frequently involve and cross the corpus callosum.
  • Approximately 4-10% of GBMs and 30-50% of AAs do not enhance, while a significant percentage of low-grade gliomas do not enhance.

Other Tests

• Functional neuroimaging such as positron emission tomography, single-photon emission computed tomography, or MR spectroscopy may help differentiate the tumor from other benign mass lesions, brain abscess, or toxoplasmosis. However, the definitive diagnosis is confirmed by stereotactic or open brain biopsy.
• Functional imaging is commonly used to differentiate between treatment-related radiation necrosis and tumor recurrence.
• Functional imaging is also used in defining the margins of the tumor for surgical resection and planning for the radiation fields.
• Additionally, functional imaging may be helpful in determining the most abnormal region of the tumor to improve the diagnostic accuracy in case a small biopsy sample is taken.

Histologic Findings

HGAs are extremely heterogenous tumors characterized by varying degrees of increased cellularity, pleomorphism, mitoses, endothelial proliferation, and necrosis.

Staging

Many different grading systems exist for gliomas. The current WHO classification of gliomas is based on the presence or absence of 4 histologic criteria: (1) nuclear atypia, (2) mitoses, (3) endothelial proliferation, and (4) necrosis. Grade I tumors have none of the criteria, grade II have one, grade III have two, and grade IV (GBM) have 3 or 4 criteria present. Prominent microvascular proliferation and/or necrosis are essential diagnostic features.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Although the prognosis of GBM is uniformly poor, treating patients in an attempt to improve the quality of life is worthwhile. Available definitive treatment options are surgery, radiotherapy, and chemotherapy. However, continuous supportive care is a major component of the medical treatment with primary brain tumors.

Surgical Care

In GBM, surgery is always an incomplete debulking, since it is a highly infiltrating tumor and cannot be resected completely. The extent of surgical resection depends on location and eloquence of the brain areas. Whether surgery prolongs survival is debatable, but several studies suggest that survival correlates more closely with the amount of residual tumor observed on postoperative MRI scans.

• After surgery, radiation therapy remains the most effective adjuvant therapy for the treatment of patients with HGA/GBM. Radiotherapy prolongs the median survival by 14-36 weeks. Different methods of administering radiation therapy are available.
• External beam radiation
• • The standard dose of external beam radiotherapy is 60 Gy in single daily fractions of 1.7-2 Gy, 5 times a week. This is applied to a limited field that includes the enhancing volume on CT scans with a 2-3 cm margin or a 1-2 cm margin beyond T2-weighted MR images.
  • Approximately 50% of AAs and 25% of GBMs decrease in size following radiotherapy. This response usually occurs by the end of treatment.
• Stereotactic brachytherapy
• • In patients who have recurrence after conventional radiotherapy, repeat resection of the tumor and brachytherapy may be indicated. Excellent candidates are patients with unifocal, well-defined, supratentorial tumors less than 5 cm in diameter that do not involve the corpus callosum, brain stem, or ependymal surfaces.
  • Brachytherapy involves using stereotactic techniques to accurately place catheters containing radioactive isotopes within brain tumors, without tumoricidal effect to normal brain tissues.
  • Typically, brachytherapy delivers an additional 50-60 Gy of radiation, bringing the total dose of radiation up to 110-120 Gy.
• Stereotactic radiosurgery
• • Stereotactic radiosurgery is a technique used to treat small ( <4 cm), radiographically well-defined lesions with a single high-dose fraction of ionizing radiation in stereotactically directed narrow beams.
  • Radiosurgery has the advantage over brachytherapy in being noninvasive, allowing treatment of patients with tumors in surgically inaccessible or eloquent areas of the brain or serious coexisting medical illnesses.
  • Preliminary results are promising.
  • Stereotactic radiosurgery has largely supplanted brachytherapy because of the invasive risks of the latter procedure.
• Boron neutron capture therapy
• • This modality of treatment is still investigational, not widely available, and costly. The value still is not proven.
  • Recently, Hatanaka treated patients with intra-arterial polyhedral borane anion and focused thermal neutron irradiation and reported a 5-year survival rate of 50% with few complications.
  • Boron neutron capture therapy for newly diagnosed or recurrent high-grade gliomas still is being evaluated.
• Chemotherapy probably has a modest but significant effect in prolonging survival when administered with concurrent radiation therapy after surgery.
• • Current recommendations include maximal possible surgical resection followed by concurrent radiation and chemotherapy with temozolomide.
  • A recent phase III randomized trial combining low-dose chemotherapy using the oral alkylating agent temozolomide concurrently with radiation, followed by an additional 6 months of adjuvant temozolomide showed statistically significant survival benefit over radiation alone. The median survival was 14.6 months with radiation therapy plus temozolomide and 12.1 months with radiation therapy alone. The treatment was well tolerated with minimal additional toxicity.
  • Another phase III randomized trial that included 240 patients compared surgery with implantation of polymer wafers with BCNU (Gliadel wafers) into the tumor bed demonstrated significant prolongation of survival compared with a placebo wafer. Both groups received radiation therapy. The median survival was 13.9 months in the group treated with Gliadel wafers and 11.6 months in the group treated with placebo.
• Extensive research is taking place on newer therapeutic options (eg, immunotherapy, antiangiogenesis, biologic therapy, growth factor and second messenger inhibition, gene therapy). These options are beyond the scope of this section. Interested readers are encouraged to read standard neuro-oncological textbooks, journals, and other sources (see Bibliography).
• For tumor recurrence, various conventional chemotherapeutic agents, including nitrosoureas, BCNU and CCNU, and chemotherapies such as cisplatin, carboplatin, etoposide, are used. Selected patients may benefit from tumor resection. Patients with recurrent GBM are encouraged to participate in approved clinical trails to develop effective regimens.
• Probably the most important part of the management of patients with GBM is compassionate and effective supportive care.
• • This care includes treatment of cerebral edema with a potent glucocorticosteroid. Dexamethasone is most commonly used because of its potent impact on edema and minimal mineralocorticoid effects. Steroid therapy often requires prophylactic use of H-2 blockers to prevent gastrointestinal side effects.
  • Seizures are a major concern with supratentorial tumors. Although seizures are less common with GBM than the low-grade glioma, treatment with appropriate anticonvulsant is uniformly recommended for a documented seizure. However, the use of a prophylactic anticonvulsant is controversial. A meta-analysis concluded that no data support the use of prophylactic anticonvulsant. Careful consideration is required in selecting an effective AED with minimal side effects and without cytochrome P450 enhancing activity because enzyme inducers can increase the metabolism and clearance of some chemotherapeutic agents.
  • Thromboembolic disease is also a major concern for patients with primary brain tumors. Although the incidence of thromboembolic disease has been reported to be as high as 35-40% during the course of the GBM, prophylactic use of anticoagulation has not been recommended because of increased risk of intracranial hemorrhage.
  • Besides the symptoms of seizures, headache, and mental status changes, many patients have neurologic deficits and require physical, occupational, and speech therapy. Frequently, patients require emotional and psychological support and benefit from help provided by support groups, local workers, psychiatrists, and organizations such as Brain Tumor Society or National Brain Tumor Foundation.

Consultations

Treatment of GBM is largely a team approach. Therefore, neurology, neurosurgery, neuro-oncology, and radiation oncology consultations should be obtained.

Diet

No special diet or limitations are required.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Alkylating agents

This oral alkylating agent has been approved for newly diagnosed GBM and recurrent anaplastic astrocytomas.

Drug Category: Cytotoxic agents

Local chemotherapy with carmustine (BCNU) wafers (Gliadel wafers) significantly prolongs survival in patients with newly diagnosed primary malignant glioma.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• After the initial definitive treatment (surgical debulking), the patient may need further inpatient care during the ongoing radiation therapy. Chemotherapy usually is performed on an outpatient basis. Continuing outpatient follow-up care is necessary if the patient develops neurological deterioration such as acute motor weakness or depression of consciousness from the effects of therapy, increased intracranial pressure from vasogenic edema, or acute hydrocephalus from ventricular obstruction. Appropriate intervention depends on the nature of the problem (eg, steroid therapy for edema, shunting for hydrocephalus).

Further Outpatient Care

• After the initial successful therapy, observe the patient regularly as an outpatient with neurologic examination and repeat MRI scans every 2 months with the chemotherapy cycles; continue every few months to follow tumor recurrence.

In/Out Patient Meds

• No specific medications are recommended for GBM. However, as mentioned previously, patients may need symptomatic therapy with steroids or anticonvulsants.

Transfer

• Transfer requirements depend on the tumor location and its response to treatment. If the tumor is in a noneloquent area and no neurological deficit is present after treatment, the patient remains fully ambulatory. However, other patients may require assistance, such as a 3-pronged cane or a wheelchair, depending on the residual neurological deficit.

Deterrence/Prevention

• No preventive measures exist for GBMs.

Complications

• During continuing follow-up care, monitor the patient closely and treat appropriately any complications that may develop. These may be caused by ongoing treatment, such as radiation necrosis and chemotherapy-induced neuropathy, or by progression of the disease, such as recurrence or leptomeningeal spread.

Prognosis

• Median survival duration for patients with GBM is 0.7 years.
• Although histologic grading remains the most important prognostic factor, other important prognostic factors include age at diagnosis and Karnofsky performance status (KPS).
• • Various studies demonstrate that patients with GBM who are younger than 40 years have an 18-month survival rate of 50%, while those aged 40-60 years have an 18-month survival rate of 20% and those older than 60 years have a rate of only 10%. In some series, age appears to be an even more important prognostic factor than histology.
  • The survival of patients with GBM decreases as KPS decreases. Patients with a KPS of more than 70 have an 18-month survival rate of 34%, while those with a KPS of less than 70 have an 18-month survival rate of 13%.
  • Additional factors such as extent of surgical resection, seizures as the initial presentation, and tumor location with superficial tumors have been variably associated with outcome.
• Recent studies are focusing attention on identifying molecular markers similar to anaplastic oligodendroglioma to predict response or resistance to specific treatments. One such interest is the expression of MGMT (O⁶-methylguanine–DNA methyltransferase) gene. The protein product of this gene, 06 alkyl guanine DNA-alkyl-transferase (AGAT), is shown to be a major mechanism for tumor resistance to alkylating agents. Recent clinical trials for malignant gliomas now often include determination of MGMT expression status. Several other molecular markers such as epidermal growth factor receptor, loss of chromosome 10, mutation or loss of the p53 gene, expression of the YKL-40 gene, loss or mutation of PTEN gene, are being investigated.

Patient Education

• During the course of diagnosis, treatment, and follow-up care, educate the patient and family about the course and prognosis of the tumor to help them cope with the physical and emotional burden. Set this goal during discussion with the patient in the presence of family members, nurses, physicians, social services, and spiritual services. In addition, frequent contacts, regular follow-up care, and involvement of support groups are necessary.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Occasionally, "butterfly-shaped" primary CNS lymphoma involving the corpus callosum may be inseparable from GBM in its clinical and radiologic presentation. Therefore, confirming the diagnosis of the suspected lesion by stereotactic biopsy (even by open biopsy in doubtful cases) is important to avoid inadvertent surgical treatment and its probable medicolegal consequences.
• Rarely, isolated large, demyelinating multiple sclerosis lesions (ie, concentric sclerosis of Balo) may be confused with and very difficult to separate from GBM by clinical presentation and radiologic appearance. Inappropriate surgical treatment may raise medicolegal actions by leaving permanent neurological deficits, which could otherwise be avoided by diligent diagnostic procedures, such as stereotactic or even open biopsy.
• Since the diagnosis of a GBM is made by histology, a pathologist experienced in diagnosis of brain tumors must examine the tissue. The current WHO classification is used in confirming the diagnosis. With neuropathologic confirmation, few difficulties are encountered in diagnosis of these tumors.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Subramanian Hariharan, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

• Bruner JM. Neuropathology of malignant gliomas. Semin Oncol. Apr 1994;21(2):126-38. [Medline].
• Burger PC, Vogel FS, Green SB, Strike TA. Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer. Sep 1 1985;56(5):1106-11. [Medline].
• Byrne TN. Imaging of gliomas. Semin Oncol. Apr 1994;21(2):162-71. [Medline].
• Colombo F, Barzon L, Franchin E, et al. Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther. Oct 2005;12(10):835-48. [Medline].
• Eagan RT, Scott M. Evaluation of prognostic factors in chemotherapy of recurrent brain tumors. J Clin Oncol. Jan 1983;1(1):38-44. [Medline].
• Gilbert MR, Loghin M. The Treatment of Malignant Gliomas. Curr Treat Options Neurol. Jul 2005;7(4):293-303. [Medline].
• Green SB, Byar DP, Walker MD, et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep. Feb 1983;67(2):121-32. [Medline].
• Kaye AH, Laws ER Jr. Brain Tumors: An Encyclopedic Approach. New York, NY: Churchill Livingtone; 1995:. 449-77.
• Kleihus P, Cavenee WK. Pathology and Genetics: Tumors of the Nervous System. Lyon, France: IARC Press; 2000:. 56-64.
• Lakka SS, Rajan M, Gondi C, et al. Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion. Oncogene. Nov 14 2002;21(52):8011-9. [Medline].
• Leibel SA, Scott CB, Pajak TF. The management of malignant gliomas with radiation therapy: Therapeutic results and research strategies. Semin Radiat Oncol. 1991;1:32-49.
• Loeffler JS, Alexander E, Wen PY, et al. Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma. J Natl Cancer Inst. Dec 19 1990;82(24):1918-21. [Medline].
• Lu KV, Jong KA, Kim GY, et al. Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem. Jul 22 2005;280(29):26953-64. [Medline].
• Macdonald DR. Adjuvant chemotherapy for brain tumor. Semin Radiat Oncol. 1991;1:54-61.
• O'Reilly SM, Newlands ES, Glaser MG, et al. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer. 1993;29A(7):940-2. [Medline].
• Pallasch CP, Struss AK, Munnia A, et al. Autoantibodies against GLEA2 and PHF3 in glioblastoma: tumor-associated autoantibodies correlated with prolonged survival. Int J Cancer. Nov 10 2005;117(3):456-9. [Medline].
• Rich JN, Hans C, Jones B, et al. Gene expression profiling and genetic markers in glioblastoma survival. Cancer Res. May 15 2005;65(10):4051-8. [Medline]. [Full Text].
• Schold SC, Burger PC, Minna JD, et al. Primary Tumors of the Brain and Spinal Cord. Boston, Mass: Butterworth-Heinemann; 1997:. 41-59.
• Sipos EP, Brem H. New delivery systems for brain tumor therapy. Neurol Clin. Nov 1995;13(4):813-25. [Medline].
• Stupp R, Mason WP. Concomitant and adjuvant temozolomide and radiotherapy for newly diagnosed glioblastoma multiforme. Conclusive results of randomized phase III trial by the EORTC brain and RT Groups and NCIC clinical trials group. American Society of Clinical Oncology. 2004;23:1.
• Valk PE, Budinger TF, Levin VA, et al. PET of malignant cerebral tumors after interstitial brachytherapy. Demonstration of metabolic activity and correlation with clinical outcome. J Neurosurg. Dec 1988;69(6):830-8. [Medline].
• Vile R, Russell SJ. Gene transfer technologies for the gene therapy of cancer. Gene Ther. Mar 1994;1(2):88-98. [Medline].
• Wallner KE, Galicich JH, Krol G, et al. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. Jun 1989;16(6):1405-9. [Medline].
• Wen PY, Fine HA, Black PM, et al. High-grade astrocytomas. Neurol Clin. Nov 1995;13(4):875-900. [Medline].
• Westermark B, Nister M. Molecular genetics of human glioma. Curr Opin Oncol. May 1995;7(3):220-5. [Medline].
• Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol. Apr 2003;5(2):79-88. [Medline].

Article Last Updated: Jan 10, 2007