User:Drealle/Sandbox



Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor, accounting for 52% of all primary 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.

Treatment can involve chemotherapy, radiotherapy, and surgery, all of which are acknowledged as palliative measures, meaning that they do not provide a cure. Even with complete surgical resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. However, many advances in microsurgery techniques, radiotherapy and chemotherapy are slowly increasing the survival time of patients diagnosed with glioblastoma.

Glioblastoma multiform can be divided into three subgroups dependent on Karnofsky Performance Score (KPS), the age of the patient, and treatment:

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. No links have been found between glioblastoma and smoking, diet , cellular phones , electromagnetic fields , or  viral infection. There appears to be a small link between ionizing radiation and glioblastoma.

Pathogenesis
Glioblastomas multiforme are characterized by the presence of small areas of necrotizing tissue that is surrounded by highly-anaplastic cells (pseudopalisading necrosis). This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features. Although glioblastoma multiforme can be formed from lower-grade astrocytomas, post-mortem autopsies have revealed that most glioblastomas multiforme are not caused by previous lesions in the brain.

Unlike oligodendrogliomas, glioblastomas multiforme can form in either the gray matter or the white matter of the brain; but most GBM arises from the deep white matter and quickly infiltrate the brain, often becoming very large before producing symptoms. The tumor may extend to the meningeal or ventricular wall, leading to the high protein content of 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 to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely rare. About 50% of GBM occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltrate 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 a nonhomogeneous mass with a hypointense center and a variable ring of enhancement surrounded by edema. Part of a lateral ventricle is usually deformed, and both lateral and third ventricles may be displaced.

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 asymptomatic until it reaches an enormous size. See Symptoms section in:

Diagnosis
In early stages, when viewed with MRI, glioblastoma may mimic more benign brain lesions. Diagnosis of a suspected GBM on CT or MRI should rest on a stereotactic biopsy or by a craniotomy, which can, at the same time, remove as much tumor as possible. Although the entire tumor can never be removed, in theory due to its multicentricity and diffuse character, partial resection ("debulking") can still prolong survival slightly.

Treatment
It is very difficult to treat glioblastoma due to several complicating factors:
 * The tumor cells are very resistant to chemotherapy and other conventional therapies
 * The brain is susceptible to damage due to 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 ninety percent of patients with glioblastoma underwent anticonvulsant treatment, although is has been estimated that only approximately 40% of patients required this treatment. Recently, it has not been recommended that neurosurgeons 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 ("debulking") is usually performed along with external beam radiation and chemotherapy.

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. It is used to take a section for 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 longer the survival time. Removal of 98% or more of the tumor has been associated with a significantly longer median survival 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.

Radiotherapy
On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve survival 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.

Chemotherapy
The standard of care for glioblastoma includes chemotherapy during and after radiotherapy. On average, chemotherapy after surgery and radiotherapy can initially reduce the tumor size to 106 cells. The use of temozolomide both during radiotherapy and for six months post radiotherapy results in a significant increase in median survival with minimal additional toxicity. This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.

Clinical trials
There are hundreds of clinical trials underway to assess the ability of new drugs and strategies to treat glioblastoma and extend the duration of survival. Below are some studies that have published promising results that have extended the survival of patients with GBM.

Pre-clinical studies

 * A possible therapy technique is to use viruses to attack the cancer. A modified herpes simplex virus has been engineered to invade tumor cells, and shows some efficacy in mice.
 * Dichloroacetate suppressed the metabolism of a glioblastoma cell line, and rats injected with a human lung cancer cell and given dichloroacetate in their drinking water had smaller tumors than the rats that did not drink dichloroacetate.

Phase I

 * Glioblastoma patients treated with motexafin gadolinium had a median survival time that was greater than a comparison group receiving standard care.
 * In recent studies, the antimalarial drug chloroquine has been shown to increase mid-term survival when given in combination with conventional therapy, although this difference did not reach statistical significance due to small sample size.
 * The use of injecting magnetic nanoparticles into the tumors of patients with recurrent GBM has been shown to be safe and feasible and resulted in promising survival rates. . Promising survival rates have been observed in animal models, however, as yet there are not any results from efficacy studies in humans.

Phase II

 * Increased intracavity treatment with the radiopharmaceutical Chlorotoxin-linked-131iodine (131-I-TM-601) has been associated with increased survival of GBM patients.
 * Intracavity treatment with Iodine131 mouse 81C6 monoclonal antibody improves survival of patients recently diagnosed with glioblastoma.
 * Microinfusion with the antisense oligonucleotide AP 12009 into the tumor site resulted in a median survival time that exceeded published baselines with conventional chemotherapy.
 * Patients receiving the radiosensitizer RSR-13 (efaproxiral) have demonstrated a slight increase in median survival, although supplemental oxygen was required during treatment due to hypoxia.
 * Patients with recurrent glioblastoma who received a combination of bevacizumab and irinotecan showed an improvement in progression-free survival compared to historical survival data.

Phase III

 * Implantation of BiCNU-impregnated wafers - trade name Gliadel - at the time of primary resection, improved median survival and prolonged the time until tumor recurrence, compared with placebo wafers.
 * Treatment of patients with newly-diagnosed glioblastoma multiforme with photodynamic therapy as an adjuvent treatment has been associated with better prognosis and improved KPS.

Recurrences
Long-term disease-free survival is unlikely, and the tumor will often reappear, usually within 2 cm of the original site, and 10% may develop new lesions at distant sites. More extensive surgery and intense local treatment after recurrence has been associated with improved survival. .

Prognosis
The median survival time from the time of diagnosis without any treatment is 3 months. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edema or increased intracranial pressure. One in twenty of glioblastoma patients survive for more than three years, and approximately one in 5,000 glioblastoma patients survive for decades. Ben Williams has now survived glioblastoma for more than twelve years.

Survival of more than three years has been associated with younger age at diagnosis, a good initial KPS, and MGMT methylation. 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 survival than patients with an unmethylated MGMT promoter. This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.

Long-term survival has 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.

Additional reading

 * Cancer Management: Brain Tumors
 * Treatment Options for Glioblastoma and other Glios