Close
Close

Glioblastoma

Gliblastoma multiforme, GBM, Grade IV astrocytoma

Overview

Glioblastoma, also known as glioblastoma multiforme (GBM) and grade IV astrocytoma, is the most common and most aggressive cancer that begins within the brain. Signs and symptoms are initially non-specific. They may include headaches, personality changes, nausea, and symptoms similar to that of a stroke. Worsening of symptoms is often rapid. This can progress to unconsciousness.

The cause of most cases is unclear. Uncommon risk factors include genetic disorders such as neurofibromatosis and Li Fraumeni syndrome and previous radiation therapy. Glioblastomas represent 15% of brain tumors. They can either start from normal brain cells or develop from an already existing low-grade astrocytoma. The diagnosis is typically made by a combination of CT scan, MRI scan, and tissue biopsy.

There is no clear way to prevent the disease. Typically treatment involves surgery after which chemotherapy and radiation therapy is used. The medication temozolomide is frequently used as part of chemotherapy. High dose steroids may be used to help reduce swelling and decrease symptoms. It is unclear if trying to remove all or simply most of the cancer is better.

Despite maximum treatment, the cancer usually recurs. The most common length of survival following diagnosis is 12 to 15 months with less than 3% to 5% of people surviving greater than five years. Without treatment survival is typically 3 months. About 3 per 100,000 people develop the disease a year. It most often begins around 64 years of age and occurs more commonly in males than females. Immunotherapy is being studied in glioblastoma with promising results.

 

Symptoms - Glioblastoma

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 - Glioblastoma

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.

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

 

 

Prevention - Glioblastoma

As the causes of GBM are unknown, there are no preventive measures.

Diagnosis - Glioblastoma

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 - Glioblastoma

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. A recent study confirms how younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. The population-based cure is thought to occur when a population's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years.

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.

 

Treatment - Glioblastoma

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 multiformeand Stevens–Johnson syndrome.
  • 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.

Surgery

Surgery is the first stage of treatment of glioblastoma. An average glioblastoma tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%). Benefits of surgery include resection for a pathological diagnosis, alleviation of symptoms related to mass effect, and potentially removing disease before secondary resistance to radiotherapy and chemotherapy occurs.

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 in retrospective analyses. The chances of near-complete initial removal of the tumor may be increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid. Gliobalstoma cells are widely infiltrative through the brain at diagnosis, and so despite a "total resection" of all obvious tumor, most people with glioblastoma later develop recurrent tumors either near the original site or at more distant locations within the brain. Other modalities, typically radiation and chemotherapy, are used after surgery in an effort to suppress and slow recurrent disease.

Radiotherapy

Subsequent to surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. It is typically performed along with giving temozolomide (TMZ). 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.

Glioblastoma tumors are well known to contain zones of tissue exhibiting hypoxia which are highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued with limited success as of 2016. As of 2010 newer research-approaches included preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate (TSC) as radiosensitizers,

and as of 2015 a clinical trial was underway.

Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.

Chemotherapy

Most studies show 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 person 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.

Antiangiogenic therapy with medications such as bevacizumab control symptoms but do not affect overall survival

Other modalities

Alternating electric field therapy is an FDA-approved therapy for newly diagnosed and recurrent glioblastoma. In 2015, initial results from a phase-three randomized clinical trial of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month improvement in progression-free survival, and a five-month improvement in overall survival compared to temozolomide therapy alone, representing the first large trial in a decade to show a survival improvement in this setting. Despite these results, the efficacy of this approach remains controversial among medical experts.


Resources - Glioblastoma

Not supplied.
Videos
by Abidemi Uruejoma
201 views
by Abidemi Uruejoma
395 views