Glioblastoma multiforme
Encyclopedia
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor
in humans, involving glial cell
s and accounting for 52% of all functional tissue
brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs occur in only 2–3 cases per 100,000 people in Europe and North America. According to the WHO classification of the tumors of the central nervous system, the standard name for this brain tumor is "glioblastoma"; it presents two variants: giant cell glioblastoma
and gliosarcoma
. Glioblastomas are also an important brain tumor in canines
, and research continues to use this as a model for developing treatments in humans.
Treatment can involve chemotherapy
, radiation, radiosurgery, corticosteroids, antiangiogenic therapy, surgery and experimental approaches such as gene transfer.
With the exception of the brainstem gliomas, glioblastoma has the worst prognosis of any central nervous system
(CNS) malignancy, despite multimodality treatment consisting of open craniotomy with surgical resection of as much of the tumor as possible, followed by concurrent or sequential chemoradiotherapy
, antiangiogenic therapy with bevacizumab
, gamma knife radiosurgery
, and symptomatic management with corticosteroids. Prognosis is poor, with a median survival time of approximately 14 months.
, nausea
and vomiting
, headache
, and hemiparesis
, the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to temporal
and frontal lobe
involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.
. No links have been found between glioblastoma and smoking
, diet
, or electromagnetic fields. Recently, evidence for a viral
cause has been discovered, possibly SV40
or cytomegalovirus
. There also appears to be a small link between ionizing radiation
and glioblastoma. Some also believe that there may be a link between polyvinyl chloride
(which is commonly used in construction) and glioblastoma. A recent link cited in the Lancet medical journal links brain cancer to lead exposure in the work place. There is an association of brain tumor incidence and malaria
, suggesting that the anopheles
mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma.
Other risk factors include:
tissue
that is surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features.
There are four subtypes of glioblastoma
. Ninety-seven percent of tumors in the ‘classical’ subtype carry extra copies of the Epidermal growth factor receptor
(EGFR) gene, and most have higher than normal expression of Epidermal growth factor receptor
(EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype. In contrast, the proneural subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor
, and in IDHl, the gene encoding isocitrate dehydrogenase
-1. The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromatosis type 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types.
GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma
or anaplastic astrocytoma
. These are called secondary GBMs and are more common in younger patients (mean age 45 versus 62 years). The tumor may extend into the meninges or ventricular
wall, leading to high protein content in the cerebrospinal fluid
(CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocyte
s. Malignant
cells carried in the CSF may spread (rarely) to the spinal cord
or cause meningeal gliomatosis. However, metastasis
of GBM
beyond the central nervous system
is extremely unusual. About 50% of GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may rarely exhibit the classic infiltration across the corpus callosum
, producing a butterfly (bilateral) glioma
.
The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis
, or its age. A CT scan will usually show an inhomogeneous mass with a hypodense center and a variable ring of enhancement surrounded by edema
. Mass effect from the tumor and edema may compress the ventricles and cause hydrocephalus
.
Cancer cells with stem cell-like properties have been found in glioblastomas (this may be a cause of their resistance to conventional treatments, and high reoccurrence rate).
.jpg)
When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as abscess
, metastasis
, tumefactive multiple sclerosis
, and other entities may have a similar appearance. Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy
or a craniotomy
with tumor resection and pathologic confirmation. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy may add value to standard MRI in the diagnosis of glioblastoma, but pathology remains the gold standard.
Treatment of primary brain tumors and brain metastases consists of both symptomatic
and palliative therapies.
neurologic function. The primary supportive agents are anticonvulsant
s and
corticosteroid
s.
and chemotherapy
. Gross total resection of tumor is associated with a better prognosis.
It is used to take a section for a pathological diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.
The greater the extent of tumor removal, the better. Removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed. The chances of near-complete initial removal of the tumor can be greatly increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid. GBM cells are widely infiltrative through the brain at diagnosis, and so despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant "satellite lesions" within the brain. Other modalities, including radiation, are used after surgery in an effort to suppress and slow recurrent disease.
Boron neutron capture therapy
has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.
. Temozolomide seems to work by sensitizing the tumor cells to radiation.
High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.
The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy based on the results of 2 studies that showed Avastin reduced tumor size in some glioblastoma patients. In the first study, 28% of glioblastoma patients had tumor shrinkage, 38% survived for at least one year, and 43% survived for at least 6 months without their disease progressing. Unlike the case for colon cancer, lung cancer and other cancers where bevacizumab acts by potentiating chemotherapy, the studies leading to approval showed that in GBM, the addition of chemotherapy to bevacizumab did not improve on results from bevacizumab alone. Bevacizumab reduces brain edema and consequent symptoms, and it may be that the benefit from this drug is due to its action against edema rather than any action against the tumor itself. Some patients with brain edema do not actually have any active tumor remaining, but rather develop the edema as a late effect of prior radiation treatment. This type of edema is difficult to distinguish from that due to tumor, and both may coexist. Both respond to bevacizumab.
A randomized Phase II clinical study with the protein therapeutic APG101
in Glioblastoma was started at the beginning of 2010. The study compares the efficacy of APG101 in a combined treatment with intravenously administered APG101 together with radiotherapy versus radiotherapy alone. APG101 is a CD95-Fc fusion protein for the treatment of malignant diseases. APG101 constitutes an innovative approach to treating GBM since it has the therapeutic aim to inhibit the invasive growth of glioblastoma cells. This therapy is based on results from the German Cancer Research Center (DKFZ) that in glioblastoma cells, the binding of the CD95-Ligand to its cognate receptor stimulates the invasive growth of the tumor cells. Thus, the inhibition of this interaction by APG101 reduces tumor cell migration. So far, APG101 has been tested in 20 healthy volunteers and 32 patients. It was well tolerated and showed no serious side effects.
has been used successfully to treat glioblastomas in a single case study. Cancer cells have impaired metabolisms and are unable to utilize fats as an energy source. They are nearly completely reliant on glucose, and glutamine to some degree, for their energy. Healthy neurons are able to utilize ketones as extremely efficient energy sources. Removing or greatly restricting carbohydrates from the diet effectively starves the cancer cells without damaging the healthy neurons. In pediatric studies, ketogenic or carb-restricted diets result in a marked decrease in tumor size and growth when used in conjunction with standard therapies.
or increased intracranial pressure
.
A good initial Karnofsky Performance Score (KPS), and MGMT
methylation
are associated with longer survival. A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the MGMT gene
is methylated. Patients with a methylated MGMT promoter have been associated with significantly greater long-term benefit than patients with an unmethylated MGMT promoter. This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.
Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy. However, much remains unknown about why some patients survive longer with glioblastoma. Age of under 50 is linked to longer survival in glioblastoma multiforme, as is 98%+ resection and use of temozolomide chemotherapy and better Karnofsky performance scores.
UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis. They are the only institution in the United States
that shows how their patients are performing. They also show a listing of chemotherapy agents used to treat GBM tumors.
According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
in humans, involving glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s and accounting for 52% of all functional tissue
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs occur in only 2–3 cases per 100,000 people in Europe and North America. According to the WHO classification of the tumors of the central nervous system, the standard name for this brain tumor is "glioblastoma"; it presents two variants: giant cell glioblastoma
Giant cell glioblastoma
The giant-cell glioblastoma is a histological variant of glioblastoma, presenting a prevalence of bizarre, multinucleated giant cells....
and gliosarcoma
Gliosarcoma
Gliosarcoma is a rare type of glioma, a cancer of the brain that comes from glial, or supportive, brain cells, as opposed to the neural brain cells. Gliosarcoma is a malignant cancer, and is defined as a glioblastoma consisting of gliomatous and sarcomatous components.It is estimated that...
. Glioblastomas are also an important brain tumor in canines
Canine brain tumors
Cancer of the nervous system is common in domestic canids, and includes primary neoplasia of the peripheral nervous system, primary neoplasia of the central nervous system and various metastatic cancers...
, and research continues to use this as a model for developing treatments in humans.
Treatment can involve chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, radiation, radiosurgery, corticosteroids, antiangiogenic therapy, surgery and experimental approaches such as gene transfer.
With the exception of the brainstem gliomas, glioblastoma has the worst prognosis of any central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) malignancy, despite multimodality treatment consisting of open craniotomy with surgical resection of as much of the tumor as possible, followed by concurrent or sequential chemoradiotherapy
Chemoradiotherapy
Chemoradiotherapy is the combination of chemotherapy and radiotherapy to treat cancer. Chemoradiotherapy in the Neoadjuvant therapy has been shown to be effective in rectal cancer....
, antiangiogenic therapy with bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
, gamma knife radiosurgery
Radiosurgery
Radiosurgery is a medical procedure that allows non-invasive treatment of benign and malignant tumors. It is also known as stereotactic radiotherapy, when used to target lesions in the brain, and stereotactic body radiotherapy when used to target lesions in the body...
, and symptomatic management with corticosteroids. Prognosis is poor, with a median survival time of approximately 14 months.
Signs and symptoms
Although common symptoms of the disease include seizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, and hemiparesis
Hemiparesis
Hemiparesis is weakness on one side of the body. It is less severe than hemiplegia - the total paralysis of the arm, leg, and trunk on one side of the body. Thus, the patient can move the impaired side of his body, but with reduced muscular strength....
, the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to temporal
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....
and frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.
Causes
GBM is more common in males, although the reason for this is not clear. Most glioblastoma tumors appear to be sporadic, without any genetic predispositionGenetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
. No links have been found between glioblastoma and smoking
Smoking
Smoking is a practice in which a substance, most commonly tobacco or cannabis, is burned and the smoke is tasted or inhaled. This is primarily practised as a route of administration for recreational drug use, as combustion releases the active substances in drugs such as nicotine and makes them...
, diet
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
, or electromagnetic fields. Recently, evidence for a viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
cause has been discovered, possibly SV40
SV40
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans...
or cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
. There also appears to be a small link between ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
and glioblastoma. Some also believe that there may be a link between polyvinyl chloride
Polyvinyl chloride
Polyvinyl chloride, commonly abbreviated PVC, is a thermoplastic polymer. It is a vinyl polymer constructed of repeating vinyl groups having one hydrogen replaced by chloride. Polyvinyl chloride is the third most widely produced plastic, after polyethylene and polypropylene. PVC is widely used in...
(which is commonly used in construction) and glioblastoma. A recent link cited in the Lancet medical journal links brain cancer to lead exposure in the work place. There is an association of brain tumor incidence and malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
, suggesting that the anopheles
Anopheles
Anopheles is a genus of mosquito. There are approximately 460 recognized species: while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus Plasmodium, which cause malaria in humans in endemic areas...
mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma.
Other risk factors include:
- Sex: male (slightly more common in men than women)
- Age: over 50 years old
- Ethnicity: Caucasians, Asians
- Having a low-grade astrocytomaAstrocytomaAstrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
(brain tumor), which often, given enough time, develops into a higher-grade tumor - Having one of the following genetic disorders is associated with an increased incidence of gliomas: NeurofibromatosisNeurofibromatosisNeurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
, Tuberous sclerosisTuberous sclerosisTuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
, Von Hippel-Lindau diseaseVon Hippel-Lindau diseaseVon Hippel–Lindau is a rare, autosomal dominant genetic condition in which hemangioblastomas are found in the cerebellum, spinal cord, kidney and retina. These are associated with several pathologies including renal angioma, renal cell carcinoma and pheochromocytoma...
, Li-Fraumeni syndromeLi-Fraumeni syndromeLi-Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. It is named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome. Li-Fraumeni syndrome greatly increases susceptibility to cancer...
, Turcot syndromeTurcot syndromeMismatch repair cancer syndrome is a condition associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome after Jacques Turcot who described the condition in 1959.-Genetics:...
Pathogenesis
Glioblastoma multiforme tumors are characterized by the presence of small areas of necrotizingNecrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
that is surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features.
There are four subtypes of glioblastoma
. Ninety-seven percent of tumors in the ‘classical’ subtype carry extra copies of the Epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) gene, and most have higher than normal expression of Epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype. In contrast, the proneural subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor
Platelet-derived growth factor receptor
Platelet-derived growth factor receptors are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including...
, and in IDHl, the gene encoding isocitrate dehydrogenase
Isocitrate dehydrogenase
Isocitrate dehydrogenase and , also known as IDH, is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while converting NAD+ to NADH...
-1. The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromatosis type 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types.
GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma
Fibrillary astrocytoma
Fibrillary astrocytomas also called low grade or diffuse astrocytomas, are a group of primary slow growing brain tumors. They typically occur in adults between the ages of twenty and fifty.-Pathology:...
or anaplastic astrocytoma
Anaplastic astrocytoma
-Symptoms:Initial presenting symptoms most commonly are headache, depressed mental status, focal neurological deficits, and/or seizures. The growth rate and mean interval between onset of symptoms and diagnosis is approximately 1.5–2 years but is highly variable, being intermediate between that of...
. These are called secondary GBMs and are more common in younger patients (mean age 45 versus 62 years). The tumor may extend into the meninges or ventricular
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...
wall, leading to high protein content in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. Malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
cells carried in the CSF may spread (rarely) to the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
or cause meningeal gliomatosis. However, metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
of GBM
GBM
-Medicine:* Glioblastoma multiforme, a type of brain tumor* Glomerular basement membrane, a part of the glomerulus which helps separate urine from blood-Other:* Game Boy Micro, a portable video game system from Nintendo...
beyond the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
is extremely unusual. About 50% of GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may rarely exhibit the classic infiltration across the corpus callosum
Corpus callosum
The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
, producing a butterfly (bilateral) glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
.
The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, or its age. A CT scan will usually show an inhomogeneous mass with a hypodense center and a variable ring of enhancement surrounded by edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
. Mass effect from the tumor and edema may compress the ventricles and cause hydrocephalus
Hydrocephalus
Hydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
.
Cancer cells with stem cell-like properties have been found in glioblastomas (this may be a cause of their resistance to conventional treatments, and high reoccurrence rate).
Diagnosis
Abscess
An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...
, metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, tumefactive multiple sclerosis
Tumefactive multiple sclerosis
Tumefactive multiple sclerosis is a condition in which the central nervous system of a person has multiple demyelinating lesions with atypical characteristics for those of standard multiple sclerosis, including a size greater than 2 cm, presence of a mass effect, edema, or ring...
, and other entities may have a similar appearance. Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy
Stereotactic biopsy
Stereotactic biopsy, also known as stereotactic core biopsy, is a biopsy procedure that uses a computer and imaging performed in at least two planes to localize a target lesion in three-dimensional space and guide the removal of tissue for examination by a pathologist under a microscope...
or a craniotomy
Craniotomy
A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often a critical operation performed on patients recording, brain imaging, and for neurological manipulations such as electrical stimulation and chemical...
with tumor resection and pathologic confirmation. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy may add value to standard MRI in the diagnosis of glioblastoma, but pathology remains the gold standard.
Treatment
It is very difficult to treat glioblastoma due to several complicating factors:- The tumor cells are very resistant to conventional therapies
- The brain is susceptible to damage due to conventional therapy
- The brain has a very limited capacity to repair itself
- Many drugs cannot cross the blood-brain barrierBlood-brain barrierThe blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
to act on the tumor
Treatment of primary brain tumors and brain metastases consists of both symptomatic
and palliative therapies.
Symptomatic therapy
Supportive treatment focuses on relieving symptoms and improving the patient’sneurologic function. The primary supportive agents are anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s and
corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s.
- Historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although it has been estimated that only approximately 40% of patients required this treatment. Recently, it has been recommended that neurosurgeons not administer anticonvulsants prophylactically, and should wait until a seizure occurs before prescribing this medication. Those receiving phenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
concurrent with radiation may have serious skin reactions such as erythema multiformeErythema multiformeErythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...
and Stevens–Johnson syndrome.
- Corticosteroids, usually dexamethasoneDexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
given 4 to 10 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood-brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.
Palliative therapy
Palliative treatment usually is conducted to improve quality of life and to achieve a longer survival time. It includes surgery, radiation therapy, and chemotherapy. A maximally feasible resection with maximal tumor-free margins is usually performed along with external beam radiationRadiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Gross total resection of tumor is associated with a better prognosis.
Surgery
Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%).It is used to take a section for a pathological diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.
The greater the extent of tumor removal, the better. Removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed. The chances of near-complete initial removal of the tumor can be greatly increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid. GBM cells are widely infiltrative through the brain at diagnosis, and so despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant "satellite lesions" within the brain. Other modalities, including radiation, are used after surgery in an effort to suppress and slow recurrent disease.
Radiotherapy
After surgery, radiotherapy is the mainstay of treatment for people with glioblastoma. A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or nonradiation therapy, those who received radiation had a median survival more than double those who did not. Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy. A total radiation dose of 60–65 Gy has been found to be optimal for treatment.Boron neutron capture therapy
Boron Neutron Capture Therapy
Boron neutron capture therapy is an experimental form of radiotherapy that uses a neutron beam that interacts with boron injected into a patient...
has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.
Chemotherapy
In other cancers where radiation can prolong survival or even cure tumors, the addition of chemotherapy to radiation improves survival over radiation treatment alone. Examples include cervical cancer, throat cancer and others. Because of this, several large clinical trials took place in which it was hoped survival of GBM patients might be improved with the addition of chemotherapy to radiation. Most of these studies showed no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone. This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. Temozolomide seems to work by sensitizing the tumor cells to radiation.
High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.
The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy based on the results of 2 studies that showed Avastin reduced tumor size in some glioblastoma patients. In the first study, 28% of glioblastoma patients had tumor shrinkage, 38% survived for at least one year, and 43% survived for at least 6 months without their disease progressing. Unlike the case for colon cancer, lung cancer and other cancers where bevacizumab acts by potentiating chemotherapy, the studies leading to approval showed that in GBM, the addition of chemotherapy to bevacizumab did not improve on results from bevacizumab alone. Bevacizumab reduces brain edema and consequent symptoms, and it may be that the benefit from this drug is due to its action against edema rather than any action against the tumor itself. Some patients with brain edema do not actually have any active tumor remaining, but rather develop the edema as a late effect of prior radiation treatment. This type of edema is difficult to distinguish from that due to tumor, and both may coexist. Both respond to bevacizumab.
Gene transfer
Gene transfer is a promising approach for fighting cancers including brain cancer. Unlike current conventional cancer treatments such as chemotherapy and radiation therapy, gene transfer has the potential to selectively kill cancer cells while leaving healthy cells unharmed. Over the past two decades significant advances have been made in gene transfer technology and the field has matured to the point of clinical and commercial feasibility. Advances include vector (gene delivery vehicle) construction, vector producer cell efficiency and scale-up processes, preclinical models for target diseases and regulatory guidance regarding clinical trial design including endpoint definitions and measurements. In one such approach, researchers at UCLA in 2005 reported a long-term survival benefit in an experimental brain tumor animal model. Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen Inc., and is currently under clinical investigation in a Phase I/II trial for the potential treatment of recurrent high grade glioma including glioblastoma multiforme (GBM) and anaplastic astrocytoma.Protein therapeutics
Not so long ago, protein therapeutics were a rarely used subset of medical treatments. Protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic — human insulin — in the early 1980s and already have a significant role in almost every field of medicine, including brain cancer.A randomized Phase II clinical study with the protein therapeutic APG101
APG101
APG101 is for the treatment of Glioblastoma multiforme .APG101 is a soluble CD95-Fc fusion protein for the treatment of malignant diseases. APG101 blocks the CD95–ligand from binding to the CD95-receptor . So far, APG101 has been tested in 20 healthy volunteers and 32 patients...
in Glioblastoma was started at the beginning of 2010. The study compares the efficacy of APG101 in a combined treatment with intravenously administered APG101 together with radiotherapy versus radiotherapy alone. APG101 is a CD95-Fc fusion protein for the treatment of malignant diseases. APG101 constitutes an innovative approach to treating GBM since it has the therapeutic aim to inhibit the invasive growth of glioblastoma cells. This therapy is based on results from the German Cancer Research Center (DKFZ) that in glioblastoma cells, the binding of the CD95-Ligand to its cognate receptor stimulates the invasive growth of the tumor cells. Thus, the inhibition of this interaction by APG101 reduces tumor cell migration. So far, APG101 has been tested in 20 healthy volunteers and 32 patients. It was well tolerated and showed no serious side effects.
Immunotherapy
Relapse of glioblastoma is attributed to the recurrence and persistance of tumor stem cells. In a small trial, a tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the disease. Larger trials are in progress to further assess this approach to treating glioblastoma.Alternating electrical fields
The use of alternating electrical fields to interfere with the division of malignant cells is a new approach to cancer treatment. As opposed to the treatment modalities of surgery, radiation and chemotherapy, which are all used to treat other types of cancer, alternating electrical fields is being explored for the first time in the treatment of glioblastoma. The underlying theory is that in an electrical field of given wavelength, cells attempting to divide will be destroyed. This approach is optimal for brain tumors in that normal brain cells do not divide, but cancer cells within the brain do. GBM patients treated with alternating electrical fields wear electrodes on the scalp attached to the portable Novo-TTF device. The recently released results of a large clinical trial of patients with relapsed GBM showed that treatment with the Novo-TTF device was at least as good as chemotherapy in prolonging survival. A currently open clinical trial for people with newly diagnosed GBM is exploring whether the addition of the Novo-TTF device to standard radiation and temozolomide treatment improves survival over standard treatment alone.Metabolic therapy
The ketogenic dietKetogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
has been used successfully to treat glioblastomas in a single case study. Cancer cells have impaired metabolisms and are unable to utilize fats as an energy source. They are nearly completely reliant on glucose, and glutamine to some degree, for their energy. Healthy neurons are able to utilize ketones as extremely efficient energy sources. Removing or greatly restricting carbohydrates from the diet effectively starves the cancer cells without damaging the healthy neurons. In pediatric studies, ketogenic or carb-restricted diets result in a marked decrease in tumor size and growth when used in conjunction with standard therapies.
Recurrences
Long-term disease-free environment is possible, but the tumor usually reappears, often within 3 cm of the original site, and 10–20% may develop new lesions at distant sites. More extensive surgery and intense local treatment after recurrence has been associated with improvement.Prognosis
The median survival time from the time of diagnosis without any treatment is 3 months, but with treatment survival of 1–2 years is common. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edemaCerebral edema
Cerebral edema or cerebral œdema is an excess accumulation of water in the intracellular or extracellular spaces of the brain.-Vasogenic:Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier...
or increased intracranial pressure
Intracranial pressure
Intracranial pressure is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid . The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF...
.
A good initial Karnofsky Performance Score (KPS), and MGMT
O-6-methylguanine-DNA methyltransferase
Methylated-DNA-protein-cysteine methyltransferase is an enzyme that in humans is encoded by the MGMT gene.- Function :O-alkyl-guanine is the major carcinogenic lesion in DNA induced by alkylating mutagens. This DNA adduct is removed by the repair protein, O-methylguanine-DNA methyltransferase...
methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
are associated with longer survival. A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the MGMT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is methylated. Patients with a methylated MGMT promoter have been associated with significantly greater long-term benefit than patients with an unmethylated MGMT promoter. This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.
Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy. However, much remains unknown about why some patients survive longer with glioblastoma. Age of under 50 is linked to longer survival in glioblastoma multiforme, as is 98%+ resection and use of temozolomide chemotherapy and better Karnofsky performance scores.
UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis. They are the only institution in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
that shows how their patients are performing. They also show a listing of chemotherapy agents used to treat GBM tumors.
According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.
| RPA class | Definition | Historical Median Survival Time | Historical 1-Year Survival | Historical 3-Year Survival | Historical 5-Year Survival |
|---|---|---|---|---|---|
| III | Age < 50, KPS ≥ 90 | 17.1 months | 70% | 20% | 14% |
| IV | Age < 50, KPS < 90 | 11.2 months | 46% | 7% | 4% |
| Age > 50, KPS ≥ 70, surgical removal with good neurologic function | |||||
| V + VI | Age ≥ 50, KPS ≥ 70, surgical removal with poor neurologic function | 7.5 months | 28% | 1% | 0% |
| Age ≥ 50, KPS ≥ 70, no surgical removal | |||||
| Age ≥ 50, KPS < 70 |
External links
- Information about Glioblastoma Multiforme (GBM) from the American Brain Tumor Association
- AFIP Course Syllabus - Astrocytoma WHO Grading Lecture Handout
- Image Database – MR & CT of Glioblastoma
- http://www.gliome.info/de – Europäisches Gliomnetzwerk EGN