Glioblastoma Multiforme

Glioblastoma multiforme is the most aggressive and common form of cancerous brain tumor in adults, affecting more than 13,000 Americans each year. Despite advances in treatment, this devastating disease remains one of the most challenging cancers to overcome, with most patients surviving only 12 to 15 months after diagnosis.

Table of contents

• What is Glioblastoma Multiforme?
• Who Gets Glioblastoma?
• Symptoms
• Causes and Risk Factors
• Diagnosis
• Treatment Options
• Prognosis and Survival
• Unique Treatment Challenges

What is Glioblastoma Multiforme?

Glioblastoma multiforme, commonly referred to as GBM or simply glioblastoma, is a fast-growing and aggressive brain tumor that starts in cells called astrocytes. These star-shaped cells are a type of glial cell that normally helps support and nourish nerve cells in the brain and spinal cord^[1].

Glioblastoma is classified as a grade IV astrocytoma, which means it is the most aggressive type of tumor on the grading scale. Brain tumors are graded from I to IV based on how fast they grow, with grade I growing very slowly and grade IV growing the fastest^[1][5].

The tumor invades nearby brain tissue but generally does not spread to distant organs outside the brain and spinal cord^[1][6]. However, it can spread to the opposite side of the brain through connection fibers or the ventricular system^[6].

In adults, glioblastoma occurs most often in the cerebral hemispheres, especially in the frontal and temporal lobes of the brain. The frontal lobes are located directly behind the forehead, while the temporal lobes are near the temples and ears inside the skull^[1][5].

Glioblastomas can arise in the brain on their own (called primary or de novo glioblastoma) or evolve from lower-grade astrocytoma (called secondary glioblastoma). Most glioblastomas are primary and tend to occur in older patients with a poorer prognosis^[1][10].

• Brain (cerebral hemispheres, frontal lobe, temporal lobe, parietal lobe, occipital lobe)
• Brain stem
• Cerebellum
• Spinal cord

Who Gets Glioblastoma?

Glioblastoma is the most common malignant brain tumor in adults, accounting for 45.2% to 47.7% of all primary malignant brain and central nervous system tumors^[1][2]. About 3 in 100,000 people develop the disease each year^[4].

The disease most often affects people between the ages of 45 and 70. The median age at diagnosis is 64 years^[1][3]. Although glioblastoma is very rare in children, it can occur at any age^[5][10].

Glioblastoma occurs more commonly in men than in women, with a ratio of about 1.6 to 1^[4][10]. The disease is also more common in Caucasians compared to other ethnicities^[10].

Symptoms

Symptoms of glioblastoma vary depending on where the tumor is located in the brain. Different areas of the brain control different functions, so the symptoms often reflect which part is affected. For example, if the tumor grows in an area that controls arm movements, the arm may become weak. If it grows in an area that controls speech, the person may have trouble forming words^[5].

Initial signs and symptoms are often nonspecific and may develop slowly or appear suddenly^[4][5]. As the tumor continues to grow, it takes up space and increases pressure within the skull, a condition called increased intracranial pressure^[5].

Common symptoms may include any of the following^[1][3][5]:

• Persistent headaches (often the first symptom)
• Double or blurred vision
• Nausea and vomiting
• Loss of appetite
• Seizures (new onset)
• Speech difficulty of gradual onset
• Changes in mood and personality
• Changes in ability to think and learn
• Memory problems
• Muscle weakness or balance issues
• Loss of coordination or trouble walking
• Sensation changes, numbness or tingling
• Fatigue
• Symptoms similar to a stroke

Many of these symptoms may be caused by other health problems. However, it is important to see a healthcare provider if you have these symptoms, as only a healthcare provider can tell if you have cancer^[5].

Symptoms often worsen rapidly and may progress to unconsciousness^[4]. If you notice any symptoms like vision changes, memory problems, headaches or seizures, visit a healthcare provider as soon as possible^[3].

Causes and Risk Factors

The cause of most cases of glioblastoma is not known^[4]. Like other brain tumors, researchers suggest that changes in DNA lead to the development of glioblastoma. Your genes contain DNA and give instructions to your cells about how to grow and multiply. Mutations, or changes, to the DNA in your genes can cause cells to multiply out of control^[3].

Most commonly, these mutations happen randomly during a person’s lifetime rather than being inherited from biological parents^[3][5]. Something happens that causes astrocytes, which are usually very controlled and organized cells, to start multiplying and forming tumors. It is not clear what causes this change^[5].

Researchers have found a number of genetic changes within tumor cells. Some of these mutations affect the ability of the cells to control themselves^[5].

The only well-established causative factor is exposure to high doses of ionizing radiation^[2]. Previous radiation therapy to the head can increase the lifetime risk of developing glioblastoma^[3][4].

Other factors that may increase risk include^[1][3][4]:

• Genetic disorders such as neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and Turcot syndrome
• Exposure to certain chemicals, like pesticides, petroleum, synthetic rubber and vinyl chloride
• Prior therapeutic radiation
• Decreased susceptibility to allergy and impaired immune response

Most people with glioblastoma have no family history or identifiable risk factors^[5]. Although it is possible to inherit genetic variations from biological parents, inherited glioblastomas are rare^[3].

Diagnosis

A healthcare provider will evaluate symptoms and perform a neurological exam. This type of exam checks vision, hearing, balance, coordination, strength and reflexes. Problems in one or more of these areas might give clues about which part of the brain the glioblastoma affects^[8].

If a brain tumor is suspected, several tests are typically performed^[3][5]:

Imaging tests can help find the location and size of a glioblastoma. Sophisticated imaging techniques can accurately pinpoint the location of brain tumors^[1][8]:

• Magnetic resonance imaging (MRI) is the most important imaging study and is the test used most often. Images are usually acquired both before and after the administration of intravenous contrast dye. As a rule of thumb, if the tumor picks up the contrast (becomes bright on images), it is an indication of a higher-grade astrocytoma. Glioblastomas display strong contrast enhancement and frequent central necrosis (areas of dead cells)^[1][2][8].
• Computed tomography (CT or CAT scan) may also be used^[1][3].
• Positron emission tomography (PET scan) can detect recurrence of the tumor^[8].
• Magnetic resonance spectroscopy (MRS) is used to examine the tumor’s chemical profile. This imaging tool provides information on the chemical composition of the tumor based on the fact that certain chemicals are abundant in normal brain, while others are abundant in tumors. This technique can be considered as a non-invasive tissue sampling, although it is not as accurate or definitive as a standard biopsy^[1][2].

Biopsy is a procedure to remove a sample of tissue for testing. It can be done with a needle before surgery or during surgery to remove the glioblastoma. The sample is sent to a lab for testing^[3][8].

The definitive diagnosis is made through a histopathological examination that reveals poorly differentiated cells with astrocytic features. High mitotic activity, microvascular proliferation, and necrosis are hallmark features of glioblastoma^[2].

Special tests of the cancer cells can give the health care team more information about the glioblastoma and prognosis. The team uses this information to create a treatment plan^[8]. Testing is also recommended for specific genetic markers and molecular characteristics^[2].

Treatment Options

The treatment of glioblastomas remains difficult, as no contemporary treatments are curative^[11]. Glioblastoma is a devastating brain cancer that can result in death in six months or less if untreated. It is imperative to seek expert neuro-oncological and neurosurgical care immediately, as this can impact overall survival^[1].

Treatment usually involves surgery, after which chemotherapy and radiation therapy are used^[4]. The gold-standard treatment comprises surgical resection followed by adjuvant radiochemotherapy^[2].

Surgery: Surgery is often the first step in treating glioblastoma and may begin treatment on an urgent, but not emergent, basis^[11][12]. The goal is to remove as much of the tumor as possible without injuring normal brain tissue or harming vital brain functions^[12][13].

Because glioblastoma invades nearby brain tissue and tumor cells quickly infiltrate surrounding tissues, complete removal is rare^[12]. However, surgical removal (decompression) of the tumor is linked to increased survival, even if only by some months^[4]. Maximal surgical resection can relieve pressure on the brain and improve symptoms^[12].

Neurosurgeons usually perform a craniotomy, opening the skull to reach the tumor site. Intra-operative mapping techniques determine the locations of motor, sensory, and speech-language areas to protect these regions during surgery^[12].

Radiation therapy: Radiation therapy uses high-energy beams to target and destroy cancer cells. It begins after the surgical site has healed and is a standard post-surgery treatment to eliminate remaining tumor tissue and slow growth^[10][12]. Typically, standard radiation therapy is given in 30 fractions (30 days) of treatment over a period of six weeks^[13].

A recent study showed promising results using short-course hypofractionated proton beam therapy incorporating advanced imaging techniques in patients over age 65. This treatment was completed in one to two weeks instead of the traditional three to six weeks and showed better outcomes than previous approaches^[15].

Chemotherapy: The primary chemotherapy drug for glioblastoma is temozolomide (TMZ), also known as Temodar. This is an oral chemotherapy pill and standard therapy that starts two to six weeks after surgery. TMZ is taken at home for 42 days, starting with or just before brain radiation. For glioblastoma, this is typically followed by six monthly cycles, though up to 12 cycles may be given^[10][12][13].

Tumor Treating Fields (TTFields): Optune is an FDA-approved wearable and portable device for adults with glioblastoma that delivers low intensity, alternating electrical fields. These fields interfere with cancer cell division, which slows or stops cancer cells from dividing and may destroy them^[13].

Targeted therapy: Some patients benefit from targeted therapy, which includes drugs that focus on specific genetic alterations in cancer cells. For example, Bevacizumab (Avastin) blocks the blood vessels necessary for tumor growth^[12].

Clinical trials: Clinical trials offer access to experimental treatments like immunotherapy or vaccine therapies for eligible patients. Many new drugs and combinations show promise in treating glioblastoma^[12]. The National Comprehensive Cancer Network recommends clinical trials for eligible patients because none of the standard treatments is curative^[11].

Supportive care: High-dose steroids may be used to help reduce swelling and decrease symptoms^[4]. Anticonvulsants are maintained to prevent seizures^[11]. Palliative care should be integrated early in the clinical course, and supportive care may be the best option for some patients^[11].

Prognosis and Survival

Glioblastoma remains an incurable disease with a median survival of 15 months even with treatment^[2]. The typical duration of survival following diagnosis is 10 to 13 months, with fewer than 5 to 10% of people surviving longer than five years^[4][12]. The five-year survival rate is about 6.9%^[23].

Without treatment, survival is typically three to four months^[4][23]. Survival is poor, with approximately 40% survival in the first year post diagnosis and 17% in the second year^[1].

Despite aggressive resection and combined modality adjuvant treatment, most glioblastomas recur^[10]. The cancer almost always recurs, and recurrences are common in up to 70 percent of glioblastoma patients^[4][21].

Prognosis varies based on factors like the patient’s age, overall health, and tumor characteristics^[12][23]. Some research has identified novel subtypes of glioblastoma that affect younger adults and have increased survival rates. In some cases, patients with tumors that have favorable genetics lived longer, with a median survival of 22 months^[7][15].

While overall mortality rates remain high, improved understanding of the molecular mechanisms and genetic mutations combined with clinical trials are leading to more promising and tailored therapeutic approaches^[11].

Unique Treatment Challenges

Glioblastomas present unique treatment challenges due to several factors^[1]:

• Localization of tumors in the brain makes surgical removal difficult without harming vital functions
• Inherent resistance to conventional therapy
• Limited capacity of the brain to repair itself
• Migration of malignant cells into adjacent brain tissue
• The variably disrupted tumor blood supply, which inhibits effective drug delivery
• Tumor capillary leakage, resulting in an accumulation of fluid around the tumor (peritumoral edema) and increased pressure within the skull
• Tumor-induced seizures
• The resultant neurotoxicity of treatments directed at gliomas
• High tumor heterogeneity and features of immune escape
• The relative immune privileged milieu of the central nervous system

Glioblastoma shows features of immune escape and high tumor heterogeneity. The relative immune privileged environment of the central nervous system, owing to the lack of antigen-presenting cells and lymphatics, further contributes to the poor prognosis among patients with glioblastoma^[2].

Glioblastoma and its treatments may affect brain function. Patients could experience mood changes and memory problems. Most people with glioblastoma eventually have to stop working and driving and may need full-time care^[3].