Glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells 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.

Signs and symptoms
Although common symptoms of the disease include seizure, 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.

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 predisposition. A viral link remains the strongest causal agent. 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:


 * Sex: male (slightly more common in men than women)
 * Age: over 50 years old
 * Ethnicity: Caucasians, Asians
 * Having a low-grade astrocytoma (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: Neurofibromatosis, Tuberous sclerosis, Von Hippel-Lindau disease, Li-Fraumeni syndrome, Turcot syndrome

Pathogenesis
Glioblastoma multiforme tumors are characterized by the presence of small areas of necrotizing 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 lymphocytes. 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).

Diagnosis
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
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 barrier 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’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.


 * 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 phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens-Johnson syndrome.


 * Corticosteroids, usually dexamethasone 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 radiation and chemotherapy. 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 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 trial. 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 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 diet has been used successfully to treat glioblastomas in several case studies. 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 most studies, ketogenic or carb-restricted diets result in a marked decrease in tumor size and growth.

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 edema 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.