User:Immunize/Treatment of glioblastoma multiforme

Glioblastoma Multiforme is an malignancy of the glial cells of the brain. It is the most common form of primary brain cancer, accounting for 12-15% of all intracranial neoplasms and 60% of all astrocytic brain tumors. Glioblastoma has a very poor prognosis and only modest improvements in therapy for glioblastoma multiforme (GBM) have been made over the past 25 years. Attention was recently drawn to this type of cancer in 2008, when senator Ted Kennedy was diagnosed with GBM. Sadly, he died of the disease in 2009.

Types of treatment
The first line of therapy for GBM is typically maximal surgical excision of the tumor. Subsequently, chemotherapy and radiotherapy are used, but now, with the advent of bevacizumab for refractory GBM, anti-angiogenic therapy is also being used. All these treatments prolong survival, with the exception of bevacizumab, which has been shown to improve progression free survival, but not overall survival.

Surgery in the treatment of GBM
the inital treatment for most patients with glioblastoma multiforme is surgical excision of the tumor for most patients, as multiple studies have indicated a survival advantage for patients who undergo resection of all visible tumor compared to those who undergo subtotal resection. However, as these tumors can not be cured with surgery alone (due to their infilterative nature), surgical goals are to obtain a pathological diagnosis, relieve mass effect, and, if possible, maximally excise the tumor to improve survival. The indications for reoperation of GBM after initial treatment with surgery, radiotherapy,and chemotherapy are not firmly established, but reoperation is often considered in the face of a life-threatening recurrent mass,or if radionecrosis rather than recurrence is suspected. Stereotatic biopsy without craniotomy may be considered in some patients, such as those whose tumors are located in sensitive areas of the brain (like the brainstem), or in those in poor medical status that precludes general anaesthesia.

Radiotherapy
Radiotherapy is a crucial part of therapy for glioblastoma multiforme, as it produces both a symptomatic and radiographic response in the majority of patients, and has been consistently shown to improve survival when compared to surgery alone. For example, in one study, radiotherapy following maximal tumor excision prolonged survival from 3–4 months (when tumor resection alone was used) to 7–12 months when both modalities were used. It appears that survival is improved when higher doses of radiation are used. In one study, for instance, use of low doses (4500 grays or less) of radiation are used, median survival is just 13 weeks, while a dose of 6000 grays of radiation produces a median survival of 40 weeks, a major improvement.

Despite the development of effective chemotheraputic and antiangiogenic agents for GBM it is expected that radiotherapy will remain an important part of GBM therapy for years to come, as it provides much higher response rates then chemotherapy or bevacizumab, and reduces GBM-related symptoms.

Chemotherapy
Chemotherapy for GBM consists largely of temozolomide therapy, as few other agents have demonstrated any benefit in GBM. Temozolomide has been proven to improve median survival in GBM,with at least one study reporting improved 2 year and median survival in patients given temozolomide + radiotherapy when compared to patients given radiotherapy alone,and it is now approved for the treatment of GBM as of march 2005. There is also a major improvement in survival in the temozolomide treated patients over patients treated with radiotherapy only (median survival in the temozolomide + radiotherapy group was 14.6, vs a median survival of 12.1 months in the radiotherapy only group), and an improved chance of being alive in 2 years (26% in the temozolomide + radiotherapy group vs 10% in the radiotherapy only group). Temozolomide is fairly well tolerated,though infertility, emesis,and other side effects do occur.

Nitrosoureas have also been researched as chemotheraputic agents in GBM, but so far, only carmustine wafers have shown any benefit to patients with GBM, and even carmustine wafers only modestly improve overall survival (median survival of 13.8 months in the carmustine treated group vs 11.6 months in the placebo group), and they did increase the risk of cerbral edema and CSF leak. In a large phase 111 trial. wafers were, however, more effective in the treatment of recurrent GBM, with one trial of the treatment showing an improvement in 6 month survival of 20% when carmustine wafers were used in patients with recurrent GBM (6 month survival in the treated group was 56% vs 6 month survival of 36% in those who were not treated with carmustine wafers). However, there was an increase in the risk of postoperative intracranial infections.

A major hindrance to the treatment of all intracranial neoplasms is that the blood brain barrier excludes many chemotheraputic agents from reaching the brain. For this reason, new methods of infusing chemotheraputic agents into the cerebrospinal fluid are being developed. Some other chemotheraputic agents,including carboplatin, cisplatin, and etoposide are sometimes used in cases of recurrent and/or refractory GBM. However, the side effects of these agents are typically much more severe then those of temozolomide.

Supportive care
Probably the most important part of the management of GBM patients is compassionate and effective supportive care, particularly for patients nearing the end of their life.

Supportive care for GBM often consists of corticosteroids and anticonvulsants, which are effective in relieving the symptoms of GBM including seizures, headaches, and somnolence.Corticosteroids are indicated for all cases of GBM, as corticosteroids relieve (and prevent) cerebral edema. Dexamethasone is the most frequently used corticosteroid because of its potent impact on edema and its minimal mineralcorticoid effects.

Seizures are a major concern in patients with CNS malignancies,and may significantly restrict the patients activities, as well as becoming life threatening on occasion. Although seizures are less common with GBM then with low-grade gliomas or anaplastic astrocytomas, anticonvulsant treatment is uniformly recommended in patients with GBM who have had a documented seizure. Prophylactic anticonvulsant use is for patients with GBM who have never had a seizure is more controversial. A 2009 study concluded that the use of prophylactic anticonvulsant drugs is not justified.

Frequently, patients experience neurologic deficits such as motor dysfunction either as a direct result of the cancer itself, or as a side effect of neurosurgery or radiotherapy. These patients often benefit from occupational or physical therapy help maximize their ability to function. Speech therapy may also benefit some patients with dysphasgia or aphasia. Some patients with GBM require psychiatric or psychological evaluation, and/or treatment for the anxiety or depression that may accompany a diagnosis of GBM.(or any other fatal disease).

Thromboembolic disease is a major concern for GBM patients. Although the incidence of thromboembolism has been reported to be as high as 35-40% in patients with GBM, prophylactic anticoagulant therapy is not recommended, as it increases the risk of intracranial hemorrhage.

Bevacizumab for glioblastoma multiforme
The FDA has approved the antiangiogenic agent bevacizumab for the treatment of GBM after 2 studies showed that bevacizumab could extend progression free survival and improve response rates in patients with recurrent or refractory GBM. The 2 studies both showed that bevacizumab had a response rate of between 20 and 26%,that in most cases lasted 4 months,a major improvement over historical controls.Also,there was improved neurocognitive function and decreased corticosteroid use in the patients who took bevacizumab,which is an compelling indication for therapy,given the devastating psychological effects of neurocognitive dysfunction on both the patient and therre familiy,and the often severe side effects of corticosteroids. "However,it remains important to remember that GBM remains incurable, although bevacizumab therapy,along with chemo-and radiotherapy can prolong survival.Bevacizumab does have side effects, including proteinuria, bowel perforation, and hemorrhage, but in the treatment of GBM, it benefits clearly outweigh it's risks. In one study, bevacizumab alone was compared against bevacizumab with the chemotherapy drug camptosar. In that study,bevacizumab and camptosar were found to be better then bevacizumab alone,with the 6 month progression free survival rate being 42% in the bevacizumab alone group compared to 50% in the bevacizumab and camptosar group. Also a reduction in detectable cancer was found in 28% of the bevacizumab only patients compared to 37% of patients  given both drugs together. Also, median survival was better in the bevacizumab and camptosar group then in the bevacizumab alone group,though the increase was not statistically significant. However,there were more serious side effects in the bevacizumab and camptosar group,so camptosar for GBM is not without its risks.

Gamma-knife radiosurgery
Despite the advent of increasingly aggressive surgery, chemotherapy, and radiotherapy in the treatment of GBM, most theraputic advances have produced only modest improvements in survival for patients with GBM. Gamma knife surgery has become an indespensible tool in the primary and adjuvant management of many intracranial pathologies,including meningiomas, pituatary tumors, and arteriovenous malformations. Although it would seem that radiosurgical treatments such as gamma knife radiosurgery, which produce very steep radiation-dose fall off around the target, would be ill-suited to treat GBM, which infiltrates surronding brain tissue,there is some evidence to suggest that gamma knife radiosurgery could play a role in the treatment of GBM. This could be attributed to the fact that most-though not all-GBM'S reccur within 2 cm of the inital tumor resection cavitiy. However,at least one randomized trial has showed no survival benefit for GBM patients treated with gamma knife surgery, tempering hope that gamma knife could be an effective modality for GBM. Yet,a retrospective study of patients treated at the university of maryland over a six year time. they observed a nearly twofold increase in the survival of GBM patients treated with gamma knife radiosurgery compared to those not getting gamma knife radiosurgery.(a median survival of 25 months for the gamma-knife treated group compared to a median survival of 13 months in those not treated with gamma knife radiosurgery). Other studies have further supported the use of gamma knife as an adjuvant therpy for  GBM.A study by Kondziolka compared their series of patients with GBM who were treated with gamma knife  radiosurgery to historical controls who recived standard therapy. In this study, patients who recieved gamma knife radiosurgery as part of the inital treatment plan had increased median survival (20 months) compared to historical controls, who had median survival of 11 months.The reasearchers also reported a median survival of 30 months for patients who had recieved gamma knife radiosurgery at the time of tumor progression. In another study, subjects with GBM were treated with gamma knife radiosurgery 2-4 weeks after external beam radiotherapy.They had a median survival of 26 months, much longer than the median survival of historical controls.

Other therapies
While the standard treatments for GBM are temozolomide chemotherapy,surgical excision,and radiotherapy (as well as bevacizumab), other treatments for GBM do exist. They include: All of these approaches are under investigation;none are yet the standard of care for GBM.
 * tyrosine kinase inhibitors.these drugs,already widely used for chronic myeloid leukemia, renal cell carcinoma and many other forms of neoplastic disease, are under investigation in GBM.
 * cancer vaccines
 * radiolabed drugs
 * synthetic chlorotoxins