Glioblastoma Multiforme (Brain Tumor)

Definition

Definition of 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.

Symptoms

Symptoms of Glioblastoma Multiforme
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

Causes of Glioblastoma Multiforme
For unknown reasons, GBM occurs more commonly in males. Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking, consumption of cured meat, or electromagnetic fields. Alcohol consumption may be a possible risk factor. 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 2006 analysis 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.

Diagnosis

Diagnosis of Glioblastoma Multiforme
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.

Prognosis

Prognosis of Glioblastoma Multiforme
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.

Treatment

Treatment of Glioblastoma Multiforme
The treatment of glioblastomas remains difficult in that no contemporary treatments are curative. While overall mortality rates remain high, recent work leading to an understanding of the molecular mechanisms and gene mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches. Multiple challenges remain, including tumor heterogeneity, tumor location in a region where it is beyond the reach of local control, and rapid, aggressive tumor relapse. Therefore, the treatment of patients with malignant gliomas still remains palliative and encompasses surgery, radiotherapy, and chemotherapy.

Upon initial diagnosis of glioblastoma multiforme (GBM), standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. For patients older than 70 years, less aggressive therapy is sometimes employed, using radiation or temozolomide alone. A study by Scott et al found that elderly patients with glioblastoma who underwent radiotherapy had improved cancer-specific survival and overall survival compared with those who did not undergo radiotherapy treatment.

Stupp et al reported the final results of the randomized phase III trial for patients with glioblastoma who were treated with adjuvant temozolomide and radiation with a median follow-up of more than 5 years. Stupp et al previously reported improved median and 2-year survival when temozolomide was added to radiation therapy in glioblastoma. Survival in the combined therapy group (ie, temozolomide and radiation) continued to exceed that of radiation alone throughout the 5-year follow-up (p< 0.0001). Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups.

Median time to recurrence after standard therapy is 6.9 months. For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or experimental therapies are also employed. A study by Wernicke et al report that prostate-specific membrane antigen is expressed in the vasculature of GBM vessels and represents a potential novel therapeutic vascular target. Future clinical trials are planned.

Symptomatic Therapy: Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

1. 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.
2. Corticosteroids, usually dexamethasone given 4 to 8 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.
• 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.
• 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.
• Metabolic Therapy: The ketogenic diet 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. This has not yet been scientifically proven and results may vary for each patient.