Glioblastoma Multiforme (GBM)

Brandon Conley, Michael Dix, Tommy Driscoll, Martin Hoogendijk, Jimmy McMullen

GBM Pathophysiology
High grade tumor that arises from glial cells, particularly astrocytes Sometimes tumors contain other cells such as oligodendrocytes and ependymal cells

GBM Pathophysiology
GBMs occur most often in the subcortical white matter of the cerebral hemispheres. In a series of 987 glioblastomas from University Hospital Zurich, the most frequently affected sites were: temporal lobe (31%) parietal lobe (24%) frontal lobe (23%) occipital lobe (16%) Combined frontotemporal location is particularly typical. It is rarely seen in cerebellum or brain stem (may make up the remaining 6%)

GBM Pathophysiology
Tumor infiltration often extends into the adjacent cortex or the basal ganglia - signs & symptoms with basal ganglia pathology? Tumors in the frontal cortex can spread across the corpus callosum into the contralateral hemisphere, creating the appearance of a symmetric lesion, called a butterfly glioma. Less common for GBM to form in brainstem, the cerebellum, and the spinal cord.

GBM Pathophysiology
Types:
1. 2.

Primary, or de novo: tumor originates in brain

tumors tend to form and present quickly. more common than secondary GBM (60% in adults older than 50) very aggressive tumors manifest de novo

Secondary: tumor cells metastasize to brain

tumors have a longer, slower growth history, but still are very aggressive may begin as lower-grade tumors (grade II) or anaplastic astrocytoma (grade III) progression time varies (months to a decade) found in people less than 45 y/o

GBM Pathophysiology
Increasing evidence indicates that primary and secondary GBM constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Of all the astrocytic neoplasms, GBM contains the greatest number of genetic changes, which, result from the accumulation of multiple mutations. Genetically, primary and secondary glioblastomas show little overlap. Studies are beginning to assess the prognosis associated with different mutations.

GBM Pathophysiology
common mutations:
- Loss of heterozygosity (LOH): most frequent gene alteration for primary and
secondary GBM (60-90%), specific mutation for GBM

- p53: tumor suppressor gene, p53 appears to be deleted or altered in approximately 25-40%
of all GBM, more common in secondary GBM

- Epidermal growth factor receptor (EGFR) gene: involved in the control of

cell proliferation. could cause overexpression of the receptor as well as rearrangements that result in truncated isoforms. mutations appear in 40-50% of primary GBM tumors.

GBM Pathophysiology
common mutations:
-MDM2:
overexpression constitutes an alternative mechanism to escape from p53regulated control of cell growth by binding to p53 to inactivate p53. This is the second most common mutation in GBM (10-15% of pts).

- Platelet-derived growth factoralpha (PDGF-alpha) gene:acts as a

major mitogen for glial cells by binding to the PDGF receptor. overexpression of PDGF receptor increases cell division in astrocytes

- PTEN: turns off signaling pathways, is consistent with possible tumor-suppression action.
Mutation results in a similar outcome as if p53 was affected

Etiology
No definitive cause Believed to be result of genetic mutations that result in uncontrollable growth of specific types of brain cells Family hx accounts for <5% of causes for developing these tumors No direct linkage between lifestyle factors and malignant gliomas (alcohol, smoking, etc) Environmental exposures

Risk Factors
The risk of developing a glioma increases if a person has any of the following genetic disorders:
Neurofibromatosis Tuberous sclerosis Von Hippel-Lindau disease Li-Fraumeni syndrome Turcot syndrome

Risk Factors
Age > 50 Having low-grade brain tumor Radiation exposure Working in the synthetic rubber or petroleum refining industries Exposure to vinyl chloride or pesticides Having had CT scans during childhood

Demographics
-Overall incidence is very similar among countries. Glioblastoma multiformes are slightly more common in the United States, Scandinavia, and Israel than in Asia. -Glioblastoma multiforme is the most frequent primary brain tumor -17,000 new cases of brain tumors diagnosed each year. 60% GBM

Demographics
-Incidence is approximately 2-3 new cases per 100,000 people per year. -3:2 male to female ratio -Most common in caucasian race -Glioblastoma multiforme may manifest in persons of any age, but it mainly affects adults, with a peak incidence at 45-70 years. -Rare in children! <1%

http://www.neurooncology.ucla.edu/Performance/GlioblastomaMultiforme.

Common Signs and Symptoms

*Note that these are the signs and symptoms of the beginning stages -Size and location dependent! Slowly progressive neurologic deficit, usually motor weakness Frequent Headaches (worse in AM or PM?) Generalized symptoms of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment Seizures personality changes

Other Signs and Symptoms

Later stages (dependent on size and location of tumor)
-Signs not sudden, may be mild at first
-Hemiparesis (contralateral to lesion and one sided/bilateral) -sensory loss (contralateral to lesion and one sided/bilateral) -difficulty walking -visual changes or loss (contralateral or ipsilateral) When would which be the case? -aphasia -memory loss

Diagnostic Imaging
Computed Tomography (CT) Scanning
may miss small tumor low grade gliomas can progress to GBM Magnetic Resonance Imaging (MRI) Positron Emission Tomography (PET) used after surgery to differentiate between
recurrent tumor tissue and scar tissue

Cerebral Angiogram

Medical Management
Surgery Chemotherapy Radiation Therapy Cutting Edge Interventions Vaccination, Tumor Treating Fields

PT Management

Preventative & Restorative Care

Starts soon after cancer has been diagnosed. Performed before or immediately after surgery, radiotherapy, or chemotherapy. Includes early intervention and education to prevent or slow down complications. The goal is to maintain a normal level of function, or to return to their prior level of function or achieve functional independence.

Supportive Care
Increases self-care ability and mobility using methods that are effective (e.g. more skillful ways of doing things) for patients whose cancer is progressing. May be implemented as a result of patients desire to not become a burden to their loved ones. Interventions can include gait training, therapeutic exercise, equipment training, and home modification.

Palliative Care
Designed to increase comfort by relieving symptoms, such as pain, dyspnea, and edema and preventing contractures and immobility issues using heat, low-frequency therapy, positioning, breathing assistance, relaxation, or the use of assistive devices. Endurance training and energy conservation techniques help the patient remain independent as long as possible. Educates the family in assisting and caring for the patient. Enables patients in the terminal stage to lead a high QOL physically, psychologically, and socially, while respecting their wishes.

Possible contributions of rehabilitation in the various phases of cancer6

Phase of disease I. Treatment Possible contributions of rehabilitation 1. Evaluating the effects of treatments on function 2. Preserving and restoring function through exercise, edema management, and increased activity 3. Controlling pain using heat, cold, and transcutaneous electrical nerve stimulation 1. Developing and supporting a program to help restore daily routines and promote a healthy lifestyle 2. Educating the patient about what to self-monitor 3. Supervising a maintenance program of exercise, edema management, and mobility management and mobility 1. Educating the patient about the impact of recurrence and its effect on function 2. Educating the patient about what to monitor in the context of the new clinical status 3. Supervising the patient in an appropriate program to restore function or prevent its decline 1. Educating patient/family regarding mobility training, good body mechanics, and A devices 2. Pain management (non-pharmacologic treatment) and symptom control 3. Maintaining independence and quality of life

II. Post-treatment

III. Recurrence

IV. End of life

Prognosis
Median survival time is 11.2 months
1 year survival is 46% 3 year survival is 7% 5 year survival is 4 % Pts with 98% of tumor removed surgically removed have significantly longer survival times. Children have a 25% 5 year survival rate

http://www.primeneurosurgery. com.au/patient-education/braintumours/glioma/glioblastomamultiforme

http://www.neurosurgery-blog. com/archives/tag/survival

http://pallipedia.org/term.php?id=484

UCSF patient makes history with brain tumor vaccine

http://abclocal.go.com/kgo/video?id=7140180

References
Glioblastoma Multiforme. NYU Langone Medical Center. Available at http://www.med.nyu.edu /content? ChunkIID=102896. 2014. Accessed March 23, 2014. 2. http://www.abta.org/brain-tumor-information/types-of-tumors/glioblastoma.html 3. https://www.aans.org/Patient%20Information/Conditions%20and%20Treatments/Glioblastoma%20Multiforme.aspx 4. http://emedicine.medscape.com/article/283252-overview#aw2aab6b2b2 5. Ann M. Berger, John L. Shuster, Jamie H. Von Roenn. Principles and Practice of Palliative Care and Supportive Oncology. Lippincott Williams & Wilkins, 2007. 6. Okamura H. Importance of rehabilitation in cancer treatment and palliative medicine. Jpn J Clin Oncol. 2011;41(6):733 738. 7. Kirshblum S, O'Dell MW, Ho C, Barr K. Rehabilitation of persons with central nervous system tumors. Cancer. 2001 Aug 15;92(4 Suppl):1029-38. 8. Reis, Eric. A Special Place: Physical Therapy in Hospice and Palliative Care. PTMagazine of Physical Therapy. March 2007. 9. Hentschel SJ, Sawaya R. Optimizing Outcomes with Maximal Surgical Resection of Malignant Gliomas. Journal of the Moffitt Cancer Center, 2003 Vol. 10, No. 2: 109-114 10. Brain tumor staging. American Society of Clinical Oncology. www.cancer.net/patient/Cancer+ Types/Brain+Tumor? sectionTitle=Staging. Accessed December 10, 2009. - See more at: http://www.uspharmacist.com/content/s/125/c/20820/#sthash. mbttoEO0.dpuf 11. Brain cancer and gliomas. WebMD. Available at http://www.webmd.com/cancer/brain-cancer/malignant-gliomas. 2014. 1.

http://www.youtube.com/watch?v=t92XSIhxmPM