Glioblastoma Multiforme

Synonyms and related keywords: glioblastoma multiforme, GBM, glioblastoma, WHO grade IV glioma, Kernohan grade IV astrocytoma, St. Anne/Mayo astrocytoma grade 4, p53, EGFR, MDM2, PDGF, PTEN, brain tumors, primary brain tumors, glial tumors, lower-grade astrocytomas, anaplastic astrocytomas, primary GBMs, secondary GBMs, astrocytic brain tumors, butterfly glioma, intracranial neoplasms, progressive neurologic deficit, motor weakness, seizures, supratentorial brain tumors, neurofibromatosis


INTRODUCTION

Background: Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Gliomas comprise a heterogeneous group of neoplasms that differ in location within the CNS, in age and sex distribution, in growth potential, in extent of invasiveness, in morphological features, in tendency for progression, and in response to treatments.

Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Composed of a heterogenous mixture of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Much less commonly, GBMs can affect the brain stem in children and the spinal cord. These tumors may develop from lower-grade astrocytomas (World Health Organization [WHO] grade II) or anaplastic astrocytomas (WHO grade III), but, more frequently, they manifest de novo, without any evidence of a less malignant precursor lesion. The treatment of glioblastomas is palliative and includes surgery, radiotherapy, and chemotherapy.

Pathophysiology: Glioblastomas can be classified as primary or secondary. Primary GBMs account for the vast majority of cases (60%) in adults older than 50 years. When these tumors manifest de novo (ie, without clinical or histopathologic evidence of a preexisting, less-malignant precursor lesion), they present after a short clinical history, usually less than 3 months.

Secondary GBMs (40%) typically develop in younger patients (less than 45 y) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, the mean interval being 4-5 years. Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Of all the astrocytic neoplasms, glioblastomas contain the greatest number of genetic changes, which, in most cases, result from the accumulation of multiple mutations.

Over the past decade, the concept of different genetic pathways leading to the common phenotypic endpoint (ie, GBM) has gained general acceptance. Genetically, primary and secondary glioblastomas show little overlap and constitute different disease entities. Studies are beginning to assess the prognoses associated with different mutations. Some of the more common genetic abnormalities are described as follows:

• Loss of heterozygosity (LOH): LOH on chromosome arm 10q is the most frequent gene alteration for both primary and secondary glioblastomas, occurring in 60-90% of cases. This mutation appears to be specific for GBM and is found rarely in other tumor grades. This mutation is associated with poor survival. LOH at 10q plus 1 or 2 of the additional gene mutations appear to be frequent alterations and are most likely major players in the development of glioblastomas.
• p53: Mutations in p53, a tumor suppressor gene, were among the first genetic alterations identified in astrocytic brain tumors. Deletion or alteration of the p53 gene appears to be present in approximately 25-40% of all GBMs. The p53immunoreactivity also appears to be associated with tumors that arise in younger patients.
• Epidermal growth factor receptor (EGFR) gene: The EGFR gene is involved in the control of cell proliferation. Multiple genetic mutations are apparent, including both overexpression of the receptor as well as rearrangements that result in truncated isoforms. However, all the clinically relevant mutations appear to contain the same phenotype leading to increased activity. These tumors typically show a simultaneous loss of chromosome 10 but rarely a concurrent p53 mutation.
• MDM2: Amplification or overexpression of MDM2 constitutes an alternative mechanism to escape from p53-regulated control of cell growth by binding to p53 and blunting its activity. Overexpression of MDM2 is the second most common gene mutation in GBMs and is observed in 10-15% of patients. Some studies show that this mutation has been associated with a poor prognosis.
• Platelet-derived growth factor–alpha (PDGF-alpha) gene: The PDGF gene acts as a major mitogen for glial cells by binding to the PDGF receptor (PDGFR). Amplification or overexpression of PDGFR is typical (60%) in the pathway leading to secondary glioblastomas.
• PTEN: PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located at band 10q23.3. The function of PTEN as a cellular phosphatase, turning off signaling pathways, is consistent with possible tumor-suppression action. When phosphatase activity is lost because of genetic mutation, signaling pathways can become activated constitutively, resulting in aberrant proliferation. PTEN mutations have been found in as many as 30% of glioblastomas.

Less frequent but more malignant mutations include the following:

• MMAC1-E1: A gene involved in the progression of gliomas to their most malignant form
• MAGE-E1: A glioma-specific member of the MAGE family that is expressed at up to 15-fold higher levels in GBMs than in normal astrocytes
• NRP/B: A nuclear-restricted protein/brain, which is expressed in neurons but not in astrocytes. NRP/B mutants are found in glioblastoma cells.

Additional genetic alterations in primary glioblastomas include p16 deletions (30-40%), p16INK4A and retinoblastoma (RB) gene protein alterations. Progression of secondary glioblastomas often includes LOH at chromosome arm 19q (50%), RB protein alterations (25%), PTEN mutations (5%), deleted-in-colorectal-carcinoma gene (DCC) gene loss of expression (50%), and LOH at 10q.

GBMs occur most often in the subcortical white matter of the cerebral hemispheres. In a series of 987 glioblastomas from University Hospital Zurich, the most frequently affected sites were the temporal (31%), parietal (24%), frontal (23%), and occipital (16%) lobes. Combined frontotemporal location is particularly typical. Tumor infiltration often extends into the adjacent cortex or the basal ganglia. When a tumor in the frontal cortex spreads across the corpus callosum into the contralateral hemisphere, it creates the appearance of a bilateral symmetric lesion, hence the term butterfly glioma. Sites for glioblastomas that are much less common are the brainstem (which often is found in affected children), the cerebellum, and the spinal cord.

Frequency:

• Internationally: GBM is the most frequent primary brain tumor, accounting for approximately 12-15% of all intracranial neoplasms and 50-60% of all astrocytic tumors. In most European and North American countries, incidence is approximately 2-3 new cases per 100,000 people per year.

Mortality/Morbidity: No significant advancements in the treatment of glioblastoma have occurred in the past 25 years. Although current therapies remain palliative, they have been shown to prolong quality survival. Mean survival is inversely correlated with age, which may reflect exclusion of older patients from clinical trials. Without therapy, patients with GBMs uniformly die within 3 months. Patients treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 12 months, with fewer than 25% of patients surviving up to 2 years and fewer than 10% of patients surviving up to 5 years. Whether the prognosis of patients with secondary glioblastoma is better than or similar to those patients with primary glioblastoma remains controversial.

Sex: In a review of 1003 glioblastoma biopsies from the University Hospital Zurich, males had a slight preponderance over females, with a ratio of 3:2.

Age: GBM may manifest at any age, but it affects adults preferentially, with a peak incidence at 45-70 years. In the series from University Hospital Zurich (a review of 1003 glioblastoma biopsies), 70% of patients were in this age group, with a mean age of 53 years. In a series reported by Dohrman (1976), only 8.8% of GBMs occurred in children.

CLINICAL

History: The clinical history of patients with glioblastoma multiformes (GBMs) usually is short, spanning less than 3 months in more than 50% of patients, unless the neoplasm developed from a lower-grade astrocytoma.

• The most common presentation of patients with glioblastomas is a slowly progressive neurologic deficit, usually motor weakness. However, the most common symptom experienced by patients is headache.

• Alternatively, patients may present with generalized symptoms of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment.

• Seizures are another common presenting symptom.

Physical: Neurologic symptoms and signs affecting patients with glioblastomas can be either general or focal and reflect the location of the tumor.

• General symptoms include headaches, nausea and vomiting, personality changes, and slowing of cognitive function.

• Headaches can vary in intensity and quality, and they frequently are more severe in the early morning or upon first awakening.

• Changes in personality, mood, mental capacity, and concentration can be early indicators or may be the only abnormalities observed.

• Focal signs include hemiparesis, sensory loss, visual loss, aphasia, and others.

• Seizures are a presenting symptom in approximately 20% of patients with supratentorial brain tumors.

Causes: Aside from the rare occurrence of familial brain tumors (eg, neurofibromatosis 1 or 2), which constitute less than 1% of all the patients with gliomas, the etiology of gliomas

DIFFERENTIALS

Mesothelioma

Other Problems to be Considered:

Anaplastic astrocytoma
Cavernous malformation
Cerebral abscess
CNS lymphoma
Encephalitis
Intracranial hemorrhage
Metastasis
Oligodendroglioma

WORKUP

Lab Studies:

• Currently, no specific laboratory studies are helpful in making a diagnosis of glioblastoma.

• Response to adjuvant therapy may be predicted by the tumor's genetics.

Imaging Studies:

• Imaging studies of the brain are essential to make the diagnosis of GBM.

• On CT scans, glioblastomas usually appear as irregularly shaped hypodense lesions with a peripheral ringlike zone of contrast enhancement and a penumbra of cerebral edema.

• MRI with and without contrast is the study of choice. These lesions typically have an enhancing ring observed on T1-weighted images and a broad surrounding zone of edema apparent on T2-weighted images. The central hypodense core represents necrosis, the contrast-enhancing ring is composed of highly dense neoplastic cells with abnormal vessels permeable to contrast agents, and the peripheral zone of nonenhancing low attenuation is vasogenic edema containing varying numbers of invasive tumor cells. Several pathological studies have clearly shown that the area of enhancement does not represent the outer tumor border because infiltrating glioma cells can be identified easily within, and occasionally beyond, a 2-cm margin.

• Positron emission tomography (PET) scans and magnetic resonance (MR) spectroscopy can be helpful to identify glioblastomas in difficult cases, such as those associated with radiation necrosis or hemorrhage. On PET scans, increased regional glucose metabolism closely correlates with cellularity and reduced survival. MR spectroscopy demonstrates an increase in the choline-to-creatine peak ratio, an increased lactate peak, and decreased N-acetylaspartate (NAA) peak in areas with glioblastomas.

• Cerebral angiograms are not necessary for the diagnosis or clinical management of glioblastomas.

Other Tests:

• Electroencephalography (EEG) performed on a patient with a GBM may show generalized diffuse slowing and/or epileptogenic spikes over the area of the tumor. However, findings specific for glioblastoma cannot be observed on EEG.

Procedures:

• Lumbar puncture generally is contraindicated in the setting of a brain tumor because of the possibility of transtentorial herniation with increased intracranial pressure. However, if ruling out lymphoma, it may be necessary.

• CSF studies do not aid significantly in the specific diagnosis of GBM.

Histologic Findings: As its name suggests, the histopathology of GBM is extremely variable. GBMs are composed of poorly differentiated, often pleomorphic astrocytic cells with marked nuclear atypia and brisk mitotic activity. Necrosis is an essential diagnostic feature, and prominent microvascular proliferation is common. Macroscopically, glioblastomas are poorly delineated, with peripheral grayish tumor cells, central yellowish necrosis from myelin breakdown, and multiple areas of old and recent hemorrhages. Most glioblastomas of the cerebral hemispheres are clearly intraparenchymal with an epicenter in the white matter, but some extend superficially and contact the leptomeninges and dura.

Despite the short duration of symptoms, these tumors often are surprisingly large at the time of presentation, occupying much of a cerebral lobe. Undoubtedly, glial fibrillary acidic protein (GFAP) remains the most valuable marker for neoplastic astrocytes. Although immunostaining is variable and tends to decrease with progressive dedifferentiation, many cells remain immunopositive for GFAP even in the most aggressive glioblastomas. Vimentin and fibronectin expression are common but less specific.

The regional heterogeneity of glioblastomas is remarkable and makes histopathological diagnosis a serious challenge when it is based solely on stereotactic needle biopsies. Tumor heterogeneity also is likely to play a significant role in explaining the meager success of all treatment modalities, including radiation, chemotherapy, and immunotherapy.

Staging: Completely staging most glioblastomas is neither practical nor possible because these tumors do not have clearly defined margins. Rather, they exhibit well-known tendencies to invade locally and spread along compact white matter pathways, such as the corpus callosum, internal capsule, optic radiation, anterior commissure, fornix, and subependymal regions. Such spread may create the appearance of multiple glioblastomas or multicentric gliomas on imaging studies.

Careful histological analyses have indicated that only 2-7% of glioblastomas are truly multiple independent tumors rather than distant spread from a primary site. Despite its rapid infiltrative growth, the glioblastoma tends not to invade the subarachnoid space and, consequently, rarely metastasizes via CSF. Hematogenous spread to extraneural tissues is very rare in patients who have not had previous surgical intervention, and penetration of the dura, venous sinuses, and bone is exceptional.

TREATMENT

Medical Care: The treatment of glioblastomas remains difficult in that no contemporary treatments are curative. While overall mortality remains high, recent work leading to an understanding of the molecular mechanisms and gene mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches. Multiple challenges remain, including tumor heterogeneity, tumor location in a region where it is beyond the reach of local control, and rapid, aggressive tumor relapse. Therefore, the treatment of patients with malignant gliomas still remains palliative and encompasses surgery, radiotherapy, and chemotherapy.

• Radiation therapy
  • Radiation therapy in addition to surgery or surgery combined with chemotherapy has been shown to prolong survival in patients with GBMs compared to surgery alone.
  • Dose response relationships for glioblastomas demonstrate that a radiation dose of less than 4500 cGy results in a median survival of 13 weeks compared with a median survival of 42 weeks with a dose of 6000 cGy.
  • The responsiveness of GBMs to radiotherapy varies. In many instances, radiotherapy can induce a phase of remission, often marked with stability or regression of neurologic deficits as well as diminution in the size of the contrast-enhancing mass. Unfortunately, any period of response is short-lived because the tumor typically recurs within 1 year, resulting in further clinical deterioration and the appearance of an expansile region of contrast enhancement.
  • Two studies investigated tumor recurrence after whole-brain radiation therapy and found that the tumor recurred within 2 cm of the original site in 90% and 78% of patients, supporting the use of focal radiation therapy. Multifocal recurrence occurred in 6% of patients in one study and in 5% of patients in a second trial.
  • Interstitial brachytherapy delivers a large dose of radiation to the tumor volume, with rapid fall-off of radiation in surrounding tissue. The tumor must be unilateral and smaller than 5 cm in diameter. In one study, patients treated with interstitial brachytherapy had a significantly better median survival (2 mo) compared with the conventional focal external beam radiation therapy. Following interstitial brachytherapy, up to 40% of patients will require another surgery for removal of tissue damaged by radiation necrosis.
  • Experimental studies are underway in which focal radiation is delivered directly to tumors through an implanted balloon containing interstitial radiation. MRI and MR spectroscopy can be used to monitor therapy. Clinical outcomes from these studies are not yet available.
  • Radiosensitizers are compounds that increase the therapeutic effect of radiation therapy. At this time, only motexafin gadolinium, a metallotexaphyrin, has been shown to increase time-to-progression when combined with radiotherapy in a phase III trial of brain metastases.

• Chemotherapy - Antineoplastics
  • Although the optimal chemotherapeutic regimen for glioblastoma is not defined at present, several studies have suggested that more than 25% of patients obtain a significant survival benefit from adjuvant chemotherapy.
  • Temozolomide is an orally active alkylating agent that is used for newly diagnosed with GBM. It was approved by the United States Food and Drug Administration (FDA) in March 2005. Studies have shown that the drug was well-tolerated and provided a survival benefit. Temozolomide with radiation was associated with significant improvements in median progression-free survival (6.9 vs 5 mo), overall survival (14.6 vs 12.1 mo), and the likelihood of being alive in 2 years (26% vs 10%).
  • Nitrosoureas: BCNU-polymer wafers (Gliadel wafers) were approved by the FDA in 2002. A phase III randomized trial that included 240 patients compared surgery with implantation of polymer wafers with BCNU 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. This increase in survival appears to be at the expense of predominantly hematologic side effects.
  • Carmustine (BCNU) and cis-platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.

• Data from the University of California at San Francisco indicate that, for the treatment of glioblastomas, surgery followed by radiation therapy leads to 1-, 3-, and 5-year survival rates of 44%, 6%, and 0%, respectively. By comparison, surgery followed by radiation and chemotherapy using nitrosourea-based regimens resulted in 1-, 3-, and 5-year survival rates of 46%, 18%, and 18%, respectively.
• A major hindrance to the use of chemotherapeutic agents for brain tumors is the fact that the blood-brain barrier (BBB) effectively excludes many agents from the CNS. For this reason, novel methods of intracranial drug delivery are being developed to deliver higher concentrations of chemotherapeutic agents to the tumor cells while avoiding the adverse systemic effects of these medications.

• Pressure-driven infusion of chemotherapeutic agents through an intracranial catheter, also known as clysis, has the advantage of delivering drugs along a pressure gradient rather than by simple diffusion. Clysis has shown promising results in animal models with agents including BCNU and topotecan.

• Initial attempts investigated the delivery of chemotherapeutic agents via an intraarterial route rather than intravenously. Unfortunately, no survival advantage was observed.

• Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies.
• A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors.

Surgical Care: The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival. In a study by Ammirati and colleagues (1987), patients with high-grade gliomas who had a gross total resection had a 2-year survival rate of 19%, while those with a subtotal resection had a 2-year survival rate of 0%.

Because these tumors cannot be cured with surgery, the surgical goals are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy. Most glioblastomas recur in and around the original tumor bed, but contralateral and distant recurrences are not uncommon, especially with lesions near the corpus callosum. The indications for reoperation of malignant astrocytomas after initial treatment with surgery, radiation therapy, and chemotherapy are not firmly established. Reoperation generally is considered in the face of a life-threatening recurrent mass, particularly if radionecrosis rather than recurrent tumor is suspected as the cause of clinical and radiographic deterioration.

Although no formal studies have been performed, observations indicate that variables, such as young age, prolonged interval between operations, and extent of the second surgical resection, have prognostic significance. PET scans and MR spectroscopy have proven useful in discriminating between these 2 entities. The median survival for anaplastic astrocytoma after reoperation in 3 series varied from 56-88 weeks.

Stereotactic biopsy followed by radiation therapy may be considered in certain circumstances. These include patients with a tumor located in an eloquent area of the brain; patients whose tumors have minimal mass effect or are infiltrating without discrete margins; and patients in poor medical condition, precluding general anesthesia. Median survival after stereotactic biopsy and radiation therapy is reported to be from 27-47 weeks.

Consultations: Patients with glioblastomas should be evaluated by a team of specialists, including a neurologist, neurosurgeon, neurooncologist, and radiation oncologist, in order to develop a coordinated treatment strategy.

Diet: No dietary restrictions are necessary.

Activity: No universal restrictions on activity are necessary for patients with glioblastomas. The patient's activity depends on his or her overall neurologic status. The presence of seizures may prevent the patient from driving. In many circumstances, physical therapy and/or rehabilitation are extremely beneficial. Activity is encouraged to reduce the risk of deep venous thrombosis.

MEDICATION

No specific medications exist to treat glioblastomas. However, certain conditions require medical treatment. For seizures, the patient usually is started on phenytoin (Dilantin) or carbamazepine (Tegretol). Vasogenic cerebral edema typically is managed with corticosteroids (eg, dexamethasone), usually in combination with some form of antiulcer agent (eg, famotidine, ranitidine). The American Academy of Neurology's practice parameters state that prophylactic antiepileptic drugs (AEDs) should not be administered routinely to patients with newly diagnosed brain tumors (standard) and should be discontinued in the first postoperative week in patients who have not experienced a seizure.

Drug Category: Anticonvulsants -- These agents are used to treat and prevent seizures.

Drug Name	Phenytoin (Dilantin) -- Acts to block sodium channels and prevent repetitive firing of action potentials. As such, it is a very effective anticonvulsant. First-line agent in patients with partial and generalized tonic-clonic seizures.
Adult Dose	Loading dose: 15 mg/kg or 1000 mg IV over 4 h divided into 2 or 3 doses Maintenance dose: 5 mg/kg/d or 300 mg PO/IV qd or divided tid; adjust dose based on serum levels
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity; effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears, and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in patients with acute intermittent porphyria and diabetes (may elevate blood sugars); discontinue use if hepatic dysfunction occurs; signs of toxicity include nystagmus, ataxia, and diplopia (necessitate lowering dose)

Drug Name	Carbamazepine (Tegretol) -- Like phenytoin, acts by interacting with sodium channels and blocking repetitive neuronal firing. First-line agent in patients with partial and tonic-clonic seizures. Serum levels should be checked and should be approximately 4-8 mcg/mL.
Adult Dose	200-600 mg PO tid/qid (bid with ER)
Pediatric Dose	15-25 mg/kg/d PO divided tid/qid (bid with ER)
Contraindications	Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d
Interactions	Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with increased IOP; obtain CBCs and serum-iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; caution while driving or performing other tasks requiring alertness; signs of toxicity include diplopia, ataxia, GI distress, and drowsiness (serum levels should be checked)

Drug Category: Corticosteroids -- These agents reduce edema around the tumor, frequently leading to symptomatic and objective improvement.

Drug Name	Dexamethasone (Decadron) -- Postulated mechanisms of action in brain tumors include reduction in vascular permeability, cytotoxic effects on tumors, inhibition of tumor formation, and decreased CSF production.
Adult Dose	16 mg/d PO/IV divided q6h, continue until patient shows improvement, taper as symptoms resolve
Pediatric Dose	0.5 mg/kg/d PO/IV divided q6h
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor for adrenal insufficiency when tapering drug because abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Category: Antineoplastic agents -- Although the optimal chemotherapeutic regimen for glioblastoma is not yet defined, several studies have suggested significant survival benefit from adjuvant chemotherapy.

Drug Name	Carmustine (BiCNU) -- Alkylates and cross-links DNA strands, inhibiting cell proliferation.
Adult Dose	100-200 mg/m2 intra-arterially 200 mg/m2 IV; not to exceed cumulative dose of 1500 mg 8 BCNU-loaded biodegradable wafers in the resection cavity
Pediatric Dose	200-250 mg/m2 IV q4-6wk
Contraindications	Documented hypersensitivity; myelosuppression from previous chemotherapy
Interactions	Coadministration with cimetidine may increase toxicity; coadministration with etoposide may cause severe hepatic dysfunction (hyperbilirubinemia, ascites, and thrombocytopenia)
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with depressed platelet, leukocyte, or erythrocyte counts or hepatic or renal impairment; perform baseline pulmonary function tests

Drug Name	Cisplatin (Platinol) -- Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.
Adult Dose	Currently, cisplatin is not administered routinely in adults with GBM because of poor penetration into CNS
Pediatric Dose	60 mg/m2 IV for 2 consecutive d q3-4wk
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur

Drug Name	Temozolomide (Temodar) -- Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier. Indicated for glioblastoma multiforme combined with radiotherapy. Significant overall survival improvement was demonstrated in patients treated with temozolomide and radiation compared with radiotherapy alone.
Adult Dose	Adjust dose according to nadir neutrophil and platelet counts from previous cycle and at time of initiating next cycle Concomitant phase: 75 mg/m2/d PO for 42-49 d with concomitant radiotherapy Maintenance cycle 1: 150 mg/m2/d PO for 5 d followed by 23 d without treatment; initiated 4 wk following concomitant phase completion Maintenance cycles 2-6: 200 mg/m2/d PO for 5 d; escalate dose from phase 1 only if blood count stable
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to temozolomide or DTIC, since each drug is metabolized to MTIC
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Causes bone marrow suppression resulting in thrombocytopenia, anemia, and leukopenia (check blood counts weekly during concomitant phase, then at day 1 and 21 of each cycle); common adverse effects include nausea, vomiting, and alopecia; not known if the drug is excreted in breast milk and because of potential serious adverse effects in infants, breastfeeding should be discontinued; PCP prophylaxis required during concomitant phase, continue if lymphocytopenia develops

FOLLOW-UP

Further Inpatient Care:

• Patients with glioblastomas who undergo surgical resection typically spend the night after surgery in an intensive care unit, followed by an inpatient stay of 3-5 days. The final length of stay depends on each patient's neurological condition.

• Postoperative antibiotics usually are continued for 24 hours, and deep vein thrombosis prophylaxis is continued until patients are ambulatory.

• Anticonvulsants are maintained at therapeutic levels throughout the inpatient stay, while steroids are reduced gradually, tailored to each patient's clinical status.

• Many patients benefit from occupational therapy and physical therapy or rehabilitation.

• While patients are in the hospital, they should receive postoperative imaging to determine the extent of surgical resection. Surgical resection is evaluated best within 3 days of surgery by using contrast-enhanced MRI. Contrast enhancement during this period accurately reflects residual tumor.

• If not performed preoperatively, complete evaluations by consulting physicians, including a neurooncologist and radiation oncologist, should be considered postoperatively.

In/Out Patient Meds:

• Patients usually are maintained on anticonvulsant medications, and levels are checked intermittently.

• Steroids are tapered to lower doses for radiation therapy and then tapered further if possible. While taking steroids, patients should be maintained on an antiulcer agent.

Transfer:

• At some institutions, transferring the patient to another facility may be necessary if the proper consultations cannot be obtained.

• In most cases, surgical resection can be performed on an urgent, but not emergent, basis.

Complications:

• Brain tumor resection has an overall mortality rate of 1-2%.

• Approximately 40% of patients have no or minimal deficits after surgery, 30% manifest no postoperative change relative to preoperative deficits, and 25% sustain an increased postoperative deficit that usually improves.

Prognosis:

• Despite extensive clinical trials, individual prediction of clinical outcome has remained an elusive goal. Glioblastomas are among the most malignant human neoplasms, with a median survival despite optimal treatment of less than 1 year. In a series of 279 patients receiving aggressive radiation and chemotherapy, only 5 of 279 patients (1.8%) survived longer than 3 years (Scott, 1998).

• Patient survival depends on a variety of clinical parameters. Younger age, higher Karnofsky performance (a standard measure of the ability of patients with cancer to perform daily tasks) score at presentation, radiotherapy, and chemotherapy all correlate with improved outcome. Clinical evidence also suggests that a greater extent of resection favors longer survival.

• Survival has not been shown to correlate with p53, EGFR, or MDM2 mutations.

• Long-term survivors, defined as those who survive longer than 2 years, are rare.

• Clearly, new approaches for the management of glioblastomas are necessary. Enrollment of patients into clinical trials will generate new information regarding investigational therapies. Novel approaches, such as the use of gene therapy and immunotherapy, as well as improved methods for the delivery of antiproliferative, antiangiogenic, and noninvasive therapies, provide hope for the future.

Patient Education:

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Because glioblastoma can be a devastating disease, meaningful communication between the physician and the patient and family is of paramount importance. To avoid medical legal pitfalls, including the patient's family in discussions regarding clinical management is essential. This often prevents family members from developing unrealistic expectations. Furthermore, communication among all the team members, including the neurosurgeon, neurologist, neurooncologist, and radiation oncologist, is important to ensure that the patient and family receive a unified treatment plan.