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Last updated: 11/17/2023
Years published: 1986, 1987, 1988, 1989, 1996, 1997, 1998, 1999, 2000, 2002, 2004, 2007, 2019, 2023
NORD gratefully acknowledges Thai Tran, NORD Editorial Intern from the Massachusetts College of Pharmacy and Health Sciences and Jeffrey N. Bruce, MD, Professor of Neurological Surgery, Columbia University Irving Medical Center, for assistance in the preparation of this report.
Summary
Glioblastomas are aggressive and malignant grade IV brain tumors that originate from the glial cells of the brain. Malignant tumors are tumors that can spread and infect other nearby cells. Glioblastomas originate from a type of glial cell called the astrocyte, so they are sometimes called astrocytoma. A grading system from I to IV defines the rate of tumor growth with grade I indicating slow growth and grade IV indicating rapid growth. Glioblastomas can often start off as grade IV tumors without any evidence of earlier lower grade tumors.
Glioblastomas can be located anywhere in the brain and do not regularly spread outside of the brain. Common symptoms patients with glioblastoma experience include headaches, seizures, confusion, memory loss, muscle weakness, visual changes, language deficit and cognitive changes. Glioblastomas tend to affect older individuals (age 45 to 70) with rare occurrences in children. Treatment methods typically include a combination of surgery, chemotherapy, radiation therapy and alternating electric fields therapy. The average survival time for patients with glioblastoma who have undergone combination treatments of surgery, chemotherapy and radiotherapy is 14.6 months.
Introduction
The World Health Organization classifies glioblastomas into three main categories. Glioblastoma isocitrate dehydrogenase (IDH)-mutant, glioblastoma IDH-wildtype and glioblastoma NOS (not otherwise specified). These classifications are based on the presence of an enzyme called IDH. Individuals with glioblastoma IDH-mutant protein in their bodies have a higher overall survival rate than those with glioblastoma IDH-wildtype protein.
Patients with glioblastoma have two types of symptoms, generalized and focal. Generalized symptoms tend to occur in many types of brain tumors. These symptoms include headaches, seizures, nausea/vomiting, memory loss and decrease in normal function. Focal symptoms are dependent on the location and size of the tumor. The size and location of the tumor often influences the signs and symptoms seen in patients. For example, if the tumor is in the part of the brain required for language processing, the patient may have more issues speaking or understanding speech. Other focal symptoms can include seizures, muscle weakness, sensory loss and visual changes.
Tumors can also cause the brain to swell because of the amount of room they take. Because they grow, they can push on parts of the brain which can lead to headaches, nausea and vomiting. Glioblastoma is an aggressive, fast-spreading tumor that affects nearby brain tissue.
The exact cause of glioblastoma is unknown. However, there are factors that can influence the risk of glioblastomas. A risk factor known to be associated with glioblastoma is prior ionizing radiation therapy that uses high energy waves or particles to destroy cancer cells but can also cause normal cells to be damaged and even lead to new cancer cells forming. Other risk factors include employment in synthetic rubber manufacturing, petroleum refining and exposure to vinyl chloride or pesticides. It is important to note that most individuals who are diagnosed with glioblastoma may not have any of these risk factors. Likewise, those with these risk factors may never develop glioblastoma in their lifetime. Causation due to risk factors has not been established and further research is needed.
Rare hereditary diseases such as Turcot syndrome, Li-Fraumeni syndrome and neurofibromatosis are associated with an increased risk of glioblastoma, but they only account for a minority of diagnoses.
3/100,000 people per year are affected by glioblastoma in the United States. The average age of diagnosis is 64 years of age with a slightly higher rate in males than females. Caucasians have the highest rate of glioblastoma diagnoses compared to other ethnic groups such as African Americans, Asians and Native Americans.
Individuals who are suspected of having a glioblastoma should first undergo a full physical and neurological examination. Neurological examinations are used to assess patient sensory and muscle responses. If any signs or symptoms of glioblastoma are present, the patient will require brain imaging using contrast-enhanced magnetic resonance imaging (MRI). MRI is often used to identify glioblastomas. It is a technique that creates detailed images of the human body. An MRI machine produces a strong magnetic field and directs radio waves towards the body. Computers interpret changes in the body caused by radio waves and produce images. Contrast dye is used to further enhance imaging. This makes it easier to distinguish tumors from normal cells. Although MRI can help identify possible glioblastomas, a tissue sample from a biopsy is required to make a definite diagnosis. A biopsy is an operation that removes tissues. A diagnosis should only be made when these tissues are confirmed to be a form of glioblastoma.
Clinical Testing and Work Up
Many factors can affect disease progression as well as the success of treatment. These include IDH-mutation status, Karnofsky performance status (KPS) and O-6 methylguanine DNA methyltransferase (MGMT) status. As noted earlier in this report, individuals with IDH-mutated genes have less aggressive tumors with better response to treatment. KPS is an assessment to determine functional capacity. The higher the score, the more activities and independence the patient can experience. A score of 100 indicates a patient can perform all tasks normally with minor signs of the disease while a score of 50 indicates that the patient requires considerable help in everyday life. Those who score higher in the KPS assessment fare better with treatment. MGMT is an enzyme responsible for DNA repair. These enzymes can influence the effectiveness of chemotherapy related to glioblastoma. Individuals with the normal form of this enzyme tend to fare better during and after chemotherapy.
Treatment
Multidisciplinary teams are essential for the treatment of glioblastomas. Each medical professional plays a critical role in treatment. These specialists include but are not limited to neuro-oncologists (diagnose and treat the disease), neurosurgeons (removes tumors), radiation oncologists (provides radiotherapy), nurses (providing necessary support and familiarity for the patient), social workers (help with any social needs), pathologists (distinguish tissue) and neuroradiologists (read MRI images). Treatment options include a combination of surgery, radiotherapy, chemotherapy and alternating electric fields therapy.
Maximal safe surgical resection of the glioblastoma is the first step in treatment. A maximally safe surgical resection means to remove as much of the tumor as possible while minimizing permanent damage to the brain. There are techniques used to increase the amount of tumor removed which include awake craniotomy, fluorescent dye, intraoperative MRI and stereotactic guidance. Awake craniotomy is performing the surgical removal of the tumor while the patient is awake. For example, if a tumor is in the part of the brain which is required for speaking, surgery in that area may cause permanent speech deterioration. By having the patient awake and speaking to the surgeon, the patient can guide the surgery and achieve better results. Fluorescent dyes help distinguish the tumor through abnormal blood vessels resulting in more of the tumor being removed. An intraoperative MRI uses radio waves and a magnetic field to create an image of the brain during the operation and is used as a guide for the removal of tumors. Stereotactic guidance functions as a GPS system that allows surgeons to precisely locate the tumor in a minimally invasive way. It is important to note that surgery is not a cure for glioblastoma. Even if an MRI shows a 100% removal of the glioblastoma tumor, there are many small undetectable tumor cells still present in the brain.
Radiotherapy, or radiation therapy, is the next step in the treatment. Radiation therapy damages the DNA of tumor cells. This slows or stops the progression of the disease. However, normal cells are also damaged by radiation therapy. Common symptoms from receiving radiation therapy include but are not limited to fatigue, loss of hair, loss of appetite and skin problems. Due to the severe side effects, radiation therapy is not continued indefinitely.
Chemotherapy can be used during and after radiotherapy as treatment for glioblastoma. Temozolomide is a therapy approved by the Food and Drug Administration (FDA) for the treatment of glioblastoma. Bevacizumab and Gliadel wafer are chemotherapy agents that have also been approved by the FDA for the treatment of glioblastoma. Bevacizumab helps reduce the number of blood vessels to the tumor site. By reducing the number of blood vessels, the tumor is unable to receive nutrients to grow. Gliadel wafer is the first approved chemotherapy agent to deliver treatment directly to the brain. These wafers are applied to the tumor site. Of these chemotherapy agents, temozolomide is the most effective for the treatment of glioblastoma.
Alternating electric fields can be used with chemotherapy, but not with radiation therapy. This treatment has been approved for both newly diagnosed and recurrent glioblastoma but with modest results. Individuals must shave their heads and electrodes are attached onto their scalp. These electrodes must stay on for most of the time, and the longer the patient undergoes treatment, the greater the potential benefits. The device generates an electric field that alternates back and forth preventing cancer cells from multiplying.
The National Comprehensive Cancer network (NCCN) guidelines encourage patients who are eligible for clinical trials to join them. These clinical trials include but are not limited to therapies directed to those who are unable to receive surgery, immunotherapy, attenuated viral therapies, targeted therapy towards tumor growth factors and the combination of these therapies.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Xu H, Chen J, Xu H, et al. Geographic Variations in the Incidence of Glioblastoma and Prognostic Factors Predictive of Overall Survival in US Adults from 2004-2013. Front Aging Neurosci. 2017;9:352. doi:10.3389/fnagi.2017.00352
Lara-Velazquez M, Al-Kharboosh R, Jeanneret S, et al. Advances in Brain Tumor Surgery for Glioblastoma in Adults. Brain Sci. 2017;7(12):166. doi:10.3390/brainsci7120166
Urbaลska K, Sokoลowska J, Szmidt M, Sysa P. Glioblastoma multiforme โ an overview. Contemp Oncol (Pozn). 2014;18(5):307-12.
Silber JR, Bobola MS, Blank A, et al. O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim Biophys Acta. 2012;1826(1):71-82.
Braganza MZ, Kitahara CM, Berrington de Gonzรกlez A, et al. Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review. Neuro Oncol. 2012;14(11):1316-24.
Martin J. van den Bent, Hendrikus J. Dubbink, Yannick Marie, et al. IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010; 16(5):1597-1604. doi:10.1158/1078-0432.CCR-09-2902
Alba A. Brandes, Alicia Tosoni, Enrico Franceschi, et al. Glioblastoma in adults. Elsevier. 2008;67(2);139-152. doi:10.1016/j.critrevonc.2008.02.005.
Roger Stupp, Warren P. Mason, Martin J. van den Bent, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005; 352:987-996. doi: 10.1056/NEJMoa043330
Chang SM, Parney IF, Huang W, et al. Patterns of Care for Adults With Newly Diagnosed Malignant Glioma. JAMA. 2005;293(5):557โ564. doi:10.1001/jama.293.5.557
INTERNET
Glioblastoma and Malignant Astrocytoma. American Brain Tumor Association. 2017. Available at: www.abta.org/wp-content/uploads/2018/03/glioblastoma-brochure.pdf Accessed Nov 8, 2023.
Glioblastoma. Genetic and Rare Diseases Information Center. Last updated: 1/19/2015. Available at: https://rarediseases.info.nih.gov/diseases/2491/glioblastoma Accessed Nov 8, 2023.
Bruce JN. Glioblastoma Multiforme. Medscape. Updated: March 7, 2023. Available at: https://www.emedicine.com/med/topic2692.htm Accessed Nov 8, 2023.
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