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Glioblastoma multiforme

Glioblastoma multiforme, (GBM) also known as grade 4 astrocytoma is the most common and aggressive type of primary brain tumor, accounting for 52 percent of all primary brain tumors cases. more...

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Treatment can involve chemotherapy, radiotherapy and surgery. The 5 year survival rate of the disease has remained unchanged over the past 30 years, and stands at less than three percent. Even with complete resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. Chromosomal aberrations like PTEN mutation, MDM2 mutation, and p53 mutation are commonly seen in these tumors. Growth factor aberrant signaling associated with EGFR, and PDGF are also seen. Tumors of this type may also infiltrate across the corpus callosum, producing a butterfly glioma.

Glioblastoma multiformes are characterized by the presence of small areas of necrotizing tissue that is surrounded by highly anaplastic cells. This characteristic differentiates the tumor from Grade 3 astrocytomas, which do not have necrotic tissue regions. Although glioblastoma multiforme can be formed from lower grade astrocytomas, post-mortem autopsies have revealed that most glioblastoma multiforme are not caused by previous lesions in the brain. Metastasis of GBM beyond the Central Nervous System is extremely rare.

A variant of glioblastoma multiforme is known as gliomatosis cerebri. Instead of a solid tumor, the cancerous cells are more scattered and diffuse. This variant preserves the architecture of the brain, but causes the affected portion of the brain to swell. It is extremely difficult to diagnose.


Although common symptoms of the disease can include seizure, headache, and hemiparesis, the single most prevalent symptom is a progressive memory, personality, or neurological deficit. The kind of symptoms produced highly depends on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is asymptomatic until it reaches an enormous size. Unlike oligodendrogliomas, glioblastoma multiformes can form in either the gray matter or white matter of the brain. The symptoms can be relieved, on a primary approach, by the administration of chorticotherapy. These drugs act by rearranging the blood-brain barrier and thus reducing brain oedema. Apart from this, not many different drugs have any kind of importance on this situation. Anti-convulsants, analgesics and stomach protection drugs are usually prescribed.

A Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan is necessary to characterize the anatomy of this tumor (size, location, heter/homogeneity). However, final diagnosis of this tumor, like most tumors, relies on histopathologic examination (biopsy examination) after biopsy or surgery.


Treatment of primary brain tumors and brain metastases consists of both supportive and definitive therapies.


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Glioblastoma multiforme
From Rehabilitation Oncology, 1/1/02 by Nguyen, Thu-Ha


* Glioblastoma is the most common primary tumor of the CNS, making up 40% to 50% of all gliomas and 11% to 13% of all brain tumors.

* The outlook for most patients with primary malignant gliomas remains bleak.

* Cure of patients with glioblastoma multiforme (GBM) remains rare, even after treatment consisting of intensive multimodality therapy.

* Ongoing neuro-oncology research is moving towards a better understanding of these tumors and providing grounds for new hope.


* In adults, the incidence of primary brain tumors in the US is approximately 17,000 new cases per year.

* Approximately 15,000 deaths a year occur in the US from malignant brain tumors.

* GBM are most common in the 45 to 55 year age group.


* Unknown

* Potential causes include: Genetic and hormonal factors

- Immunological disorders

- Environmental influences

- Viral induction

- Prior radiation therapy

- Mutation


* Astrocytes: -most numerous, most elaborate, and largest of the glial cells

- form most of the supportive tissue for the neurons

- nourish the neurons and regulate the chemical environment

- form the blood-brain barrier

* Malignant cells interrupt and destroy normal neuronal pathways and function.

* Cellular composition is heterogeneous (multiforme).

* Macroscopically: large and well circumscribed with a variegated pattern on the cut surface, a peripheral rim of pinkish-- gray solid tumor and soft yellow necrotic tissue center, often with points of hemorrhage.

* Microscopically: increased cellularity, vascular proliferation, cellular pleomorphism, and necrosis with pseudopalisading.

* Necrosis is considered the histologic hallmark of GBM.

* Metastasis within and outside the CNS is rare. GRADING OF ASTROCYTOMAS

* Tumors are graded by the extent of exhibits.

* Two widely used tumor classification systems are:

* Kernohan's four-tier system

* Rigertz's three-tiered system (WHO) NEUROLOGIC SIGNS AND SYMPTOMS

* Neurologic signs & symptoms of an astrocytoma occur due to displacement of normal brain tissue by the increase in tumor size or by blockage of normal flow of CSR

* Often subtle at the onset (may develop over 1-10 years before symptoms occur).

* Understanding the physiological basis for signs and symptoms will assist health care practitioners in assessment and patient/family education.

* Signs and Symptoms

* Headache (present in approx 72% of patients)

* GI upset with loss of appetite/nausea/vomiting

* Slowing of cognitive function

* Mental confusion and personality changes (ie, lethargy, irritability, emotional lability, and decreased memory)

* Focal neurologic deficits depending on tumor location include hemiparesis, visual or speech deficits, cranial nerve dysfunction, and motor weakness

* Seizures

* Papilledema


* Advances in diagnostic tools, health care practitioners are able to confirm the presence of a lesion, pinpoint its location and size, and assess its impact on surrounding structures.


* Most commonly used and probably the most accurate in tumor diagnosis (80% to 90% accuracy).

* The malignant glioma appears as a mass lesion with ring-like enhancement pattern surrounded by white matter edema and a non-enhancing necrotic core.


* Helps characterize abnormality and distinguish edema and radiation-induced changes from residual or recurrent tumor.

* Provide a clearer visualization of the tumor in different planes (axial, coronal, sagittal).


* Cerebral angiography demonstrates the neovascularity of malignant gliomas.


* Evaluates tumor metabolism (radiation necrosis vs. recurrent tumors)


* Histological diagnosis.

* Accurate diagnosis is important for several reasons:

* Individual patient prognosis depends critically on histologic diagnosis.

* The type and grade of a tumor is taken into account when formulating treatment plans.

* Stereotactic biopsy provides small specimens leading to sampling error.

* A study by Glantz et al suggests that biopsy leads to underestimation of the histologic grade of anaplastic gliomas.

* Approximately 30% of biopsies result in an inaccurate diagnosis.

* Indications for stereotactic biopsy:

* Permits tissue diagnosis in patients unable to tolerate craniotomy (elderly debilitated patients or those who are poor surgical candidates).

* In tumors located too strategically (deep cerebral or brain stem lesions) to allow resection.

* Thorough patient and family education should be accomplished prior to the diagnostic procedures so both patient and family know what to expect before, during, and after testing.


* Malignant tumors are heterogeneous tumors; therefore, each tumor responds to therapy differently.

*Individualized management is necessary with the goals of treatment being to improve the patient's quality of life, survival time, and symptomatic relief.

*There is no guarantee of cure and treatment can be painful and debilitating.

* Type of therapy chosen depends on tumor location, histologic grade, signs & symptoms present, functional status (KPS), age, and whether the tumor is recurrent.

* No matter what treatment option is chosen, the patient and family should be informed of what they may expect as side effects from treatments as well as what benefits may be achieved.

Three main treatment options are used for GBM: 1. Surgery

* Over the past decade, neurosurgical instrumentation has improved tremendously facilitating safer tumor resection with preservation of neurological function.

* Decisions regarding the optimal surgical approach are based on the purpose of surgery, age, neurological condition, medical/surgical risk factors, tumor characteristics/ location, and physician's preference.

* Assess both physical and emotional readiness for surgery.

* The more extensive the tumor resection the longer the survival rate.

* Lacroix et al found that a significant survival advantage was associated with resection of 98% or more of the tumor volume.

* Tumors located close to the brain surface, large lesions, and those with significant edema that produce mass effect may benefit from craniotomy for gross total resection.

* Total excision of astrocytomas is almost impossible to achieve due to the ill defined border between tumor and normal tissue.

* Deep lesions, those in eloquent areas of the brain or multiple tumors may best be addressed with stereotactic biopsy. * Maximum safe resection is the initial treatment for primary malignant gliomas.

* Goals of surgery include: * establishing a histologic diagnosis,

* provide symptomatic relief of increased ICP/improvement of neurological symptoms,

* increasing the duration of high-quality survival, and

* enhance the effectiveness of other therapy (removal of hypoxic radio-resistant neoplastic cells).

2. Radiotherapy

* Radiotherapy, while not curative, may enhance survival in the short term.

* Patients treated by both surgery/radiotherapy had a longer median survival.

* Jubelirer found that radiotherapy was a significant predictor of survival.

* GBM patients have a I to 2 year survival rate after radiation, but 5 year survival rate was 0% with or without radiation.

* Radiotherapy is usually performed postoperatively in an attempt to destroy remaining tumor cells.

* Radiation also may be used without surgery when tumors are surgically inaccessible or to decrease tumor size prior to surgical resection.

* The amount of radiation the patient receives depends on the histological type of the tumor, its radioresponsiveness, location, and the patient's level of tolerance.

* Normal course of therapy is 2 Gy 5 days a week, for 6 weeks; total tumor dose of 60 Gy.

* Adverse effects of radiation include:

* nausea/vomiting, diarrhea, anorexia, general malaise, increased headache, alopecia, skin breakdown at the radiation site, and decrease in self esteem from the resulting adverse effects.

* Radiation necrosis, an irreversible and often progressive degeneration of the white matter at the tumor site and surrounding irradiated brain.

3. Chemotherapy

* Although surgery is an important treatment modality, tumor cells almost invariably remain after aggressive attempts at surgical removal. Radiation therapy prolongs survival, but tumor recurrence is usually evident in months.

* Chemotherapy has primarily been used in an adjuvant setting after radiation therapy for primary brain tumors.

* Chemotherapy may be given through the intravenous, intra-arterial, intraventricular, intrathecal, or intratumoral route.

* Most common adverse effects of conventional chemotherapy include:

* Nausea, vomiting, diarrhea, alopecia, stomatitis, bone marrow depression, anorexia, amenorrhea, and a decrease in fertility.

* Hepatotoxicity and nephrotoxicity.

* Decrease in self esteem and need emotional support.

* Choice of a chemotherapeutic agent also depends on tumor type, location, and the patient's reaction after starting the drug. Carmustine (BCNU) is a common chemotherapeutic agent used.

* When treating brain tumors, the chemotherapeutic agent must cross the blood-brain barrier to be effective. However, it is difficult to achieve adequate exposure to the tumor without systemic toxicity (bone marrow suppression, liver, and renal toxicity).

* BCNU impregnated wafers (Gliadel):

* Their rationale behind this approach was based on the high local recurrence rate of primary brain tumors, the restrictions to systemic drug delivery imposed by the BBB, and the severe complications from systemic exposure to drugs targeted for the brain.

* Time-released wafer, which is the size of a quarter and implanted directly into the resected tumor cavity at the time of craniotomy.

* Allows controlled prolonged local exposure during a period of approximately 2 weeks.

* Brem and colleagues conducted a randomized placebo controlled study and found the BCNU wafers to be safe and effective in treatment of recurrent malignant gliomas.

* A study by Valtonen and colleagues concluded that BCNU applied locally in a biodegradeable polymer at the time of primary operation, seems to have a favorable effect on the life span of patients with high-grade gliomas. The most frequently documented adverse effects were hemiparesis, convulsions, and visual field deficits but were not significantly different in the two groups.

* Advantages of BCNU loaded polymers include:

* high local concentrations,

* systemic toxicity would be minimized,

* inconsistent delivery of systemically administered agents through variably intact BBB would be eliminated,

* ease of use (procedure itself only takes a few minutes),

* time of hospitalization is not prolonged,

* administration of the drug did not have any negative effect on the patient's quality of life, and

* controlled delivery of chemotherapy using biodegradable polymers is a valuable addition to the neurosurgical armamentarium.

* Steroids - Administered for cerebral edema and increased ICP.

* Analgesics - Administered for relief of headaches.

* Anticonvulsants - Used for seizure management.

* Patients and family may decide against surgery and further treatment. As health care professionals, we must provide adequate information so the patient and family can give informed consent, and support them in their decision.


* Although survival is positively correlated with the degree of tumor resection and radiotherapy, all malignant astrocytomas will eventually recur.

* Must distinguish XRT side effects from recurrence.

* Chemotherapy and radiotherapy is necessary to forestall recurrence, resulting in increased quality and duration of survival. When tumor recurrence is accompanied by significant intellectual and functional decay, patients benefit most from compassionate care, in which patient comfort, not survival, becomes the primary consideration.


* Prognosis for these patients is poor.

* Several variables affect the prognosis of patients with GBM including:

* Age;

* preoperative performance status according to the KPS;

* tumor location;

* whether the patient undergoes reoperations for recurrent tumor;

* whether the patient receives surgery, radiation therapy, or chemotherapy;

* radiation response; and

* extent of resection.


* PT should be aware of all complications that can result postoperatively as well as during radiation and chemotherapy.

* Emotional support for the patient and family should be offered. Inpatient care

* A detailed history and a physical examination are the basis of every patient evaluation, and will aid in decision-making.

* Monitor vital signs and ICP.

* Complete neurological examination as a baseline and at regular intervals to assess neurological changes. Early detection of deterioration can improve the likelihood of successful intervention.

* Discharged planning begins immediately; assess home environment and anticipated discharge needs (DME, OT, PT).

* Discuss course of treatment with patient and family.

* PT treatment may consist of ROM, bed mobility/transfers, strengthening, and gait training with the least restrictive device.

* Patients are generally ambulatory the day after surgery, are able to resume previous dietary and medication routines, and may engage in activity as tolerated.

* Discuss realistic goals of therapy with patient and family.

* PT should be knowledgeable about the pathology, classification, diagnostic procedures, and treatment options.

* Patient/family education and emotional support are very important. Much psychological support is needed at this time.

* As patient advocates, we must strive to maintain and improve quality of care and quality of life.

* Caring for patients with CNS tumors is a challenging and rewarding aspect of PT.


Adams BA, Clancy JK, Eddy M. Malignant glioma: Current treatment perspectives. J Neurosci Nurs. 1991;23(1):15-19.

Bohan EM. Neurosurgical management of patients with central nervous system malignancies. Semin Oncol Nurs. 1998;14(l):8-17.

Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995;345:1008-1012.

Glantz MJ, Burger PC, Hemdon JE, Friedman AH, Cairncross JG. Influence of the type of surgery on the histologic diagnosis in patients with anaplastic gliomas. Neurology. 1991;41:17411743.

Jubelirer SJ. A review of the treatment and survival rates of 138 patients with glioblastoma multiforme. W V Med J. 1996;92(4):186-190.

Chamberlain MC, Kormanik PA. Practical guidelines for the treatment of malignant gliomas. West J Med. 1998; 168(2):114-120.

Greenberg MS. Handbook of Neurosurgery. 3rd ed. Lakeland, Fla: Greenberg Graphics, Inc.; 1994.

Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. J Neurosurg. 2001;95:190-- 198.

Schnell S, Maher de Leon ME. Anatomy of the central nervous system. Sem Oncol Nurs. 1998;14(1):2-7.

Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high grade gliomas: A randomized double-blind study. Neurosurgery. 1997;41:44-48.

Willis D. Intracranial astrocytoma: Pathology, diagnosis and clinical presentation. J Neurosci Nurs. 1991;23(1):7-14.

Thu-Ha Nguyen, SPT

MCV Cancer Rehabilitation

Medical College of Virginia

Richmond, Virginia

Copyright Rehabilitation in Oncology 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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