Background Glioblastoma (previously known as glioblastoma multiforme or GBM) is the most common incurable primary brain malignancy in adults. This Fast Fact addresses symptom management, prognosis, and medical decision-making in glioblastoma patients. 

Prognosis   Median age at diagnosis is 64; median survival from diagnosis is 15 months. Extended survival may be seen with favorable genetic mutations (e.g. MGMT and IDH), age < 50 years, and a fully independent postoperative functional status (1,2). Two-year survival after diagnosis is 27%; 5-year survival is 10% (3). Its illness trajectory is associated with a rapid rate of cognitive decline preceding the steep functional decline indicative of the usual dying phase of cancer. 

Symptom Presentation and Management   Tumor size, tumor location, and cancer treatment side effects are the most common determinants of how symptoms manifest.

• Focal deficits. Hemiparesis, aphasia, paresthesias, dysarthria, dysphagia, visual changes, and neglect are common. Management includes physical, occupational and speech therapy, psychosocial support, and corticosteroids (e.g. dexamethasone 2-4 mg daily or twice a day) (2,4).
• Cognitive changes. Depression and anxiety are common; hence many glioblastoma patients are initiated on antidepressants. Memory loss, personality changes, fatigue, agitation, and delirium are also common. Management options include psychotropics, assessment of decision-making capacity, and off-label use of psychostimulants for depression, apathy, or drowsiness (see Fast Fact #173) (5,6). While corticosteroids can help with vasogenic-related symptoms such as headaches or nausea, they can exacerbate behavioral changes via psychiatric side effects (see Fast Fact # 323).
• Seizures.  Even though seizures are a common presenting sign of glioblastoma, prophylactic antiepileptic drugs (AEDs) are not recommended. Instead, active seizures are treated with benzodiazepines, and AEDs are initiated thereafter.  Consultation with a clinical pharmacist or a neurologist is advised to minimize drug interactions and identify appropriate routes of administration for AEDs.  At the end-of-life, oral administration may not be feasible. See Fast Fact #229 for more information on rectal, sublingual, subcutaneous, or intravenous routes (2,11,2).
• Headache, nausea, and fatigue.  These symptoms can result from the effects of chemotherapy or radiation therapy or from a disease-related increase in the intracranial pressure (ICP).  Beyond conventional treatments, corticosteroids may help if vasogenic edema is present; radiation therapy and ventriculoperitoneal shunts can help manage increased-ICP-related symptoms (2,4,7). 

Cancer-Directed Therapy   For newly diagnosed patients with a preserved performance status, standard treatment involves maximal safe surgical resection followed by concomitant temozolomide (TMZ) chemotherapy and 6 weeks of radiotherapy (2,3). Essentially all patients will experience disease recurrence for which no standard treatment exists (1,2). Instead, various strategies are individualized.

• Any combination of repeat surgical resection, re-irradiation, and chemotherapy (TMZ or other) (8). 
• Bevacizumab: A monoclonal antibody that can yield radiographic improvement of the tumor and thereby reduce functional deficits and the need for corticosteroids.  Although it may improve quality of life, current data shows it does not prolong survival and can precipitate strokes and cardiovascular events via side effects including bleeding and clotting (9,10).
• Tumor Treating Fields (TTF):  A headpiece that is worn 24 hours per day and applies low-intensity alternating electric fields to disrupt cell division of cancer cells. TTF is a new treatment with relatively limited evidence to suggest it can prolong survival when combined with TMZ for newly diagnosed and recurrent glioblastoma (12). The cosmetic appearance and burden of wearing a device all day, is a considerable trade-off that may impact quality of life.
• Hospice is an appropriate care plan for any patient with recurrent glioblastoma, particularly those with comfort-based goals of care and/or a poor performance status.

Medical-Decision Making   Deciding when to stop life prolonging treatment can be challenging in glioblastoma. As with any other type of cancer or life-limiting illness, this should be a shared-decision between patients and clinicians based on performance status, treatment expectations, and quality of life preferences. Below are additional medical-decision-making elements worth highlighting for glioblastoma:

• In most cases, patients will not be able to enroll in hospice if they are continuing anti-cancer treatments like radiation or chemotherapy. There is some controversy around abruptly stopping bevacizumab for fear of rebound vasogenic edema contributing to a faster decline. Despite these concerns, bevacizumab is associated with its own side effects (loss of appetite, nausea, constipation, bleeding, clotting) and burdens. Hence, most experts recommend its discontinuation in the event of tumor progression so that patients can maximize their access to hospice support (11).
• Close collaboration with treating oncologists is crucial when interpreting tumor status on radiologic imaging, as microscopic progression may make radiologic interpretation challenging (11).
• Given the high risk for early cognitive changes, early advance care planning (ACP), including identification of a surrogate decision-maker, is critical with glioblastoma. ACP discussions should begin at diagnosis, and be revisited at oncologic touch points such as completion of first-line treatment, disease recurrence, hospitalizations, and any decline in functional status (6,13,14). 
• Disease-related behavioral and/or cognitive changes can lead to caregiver burden and make home hospice dispositions challenging. This can create caregiver guilt, especially for patients who expressed a wish to die at home. Clinicians may need to support surrogates by highlighting the patient care needs and the safety benefits of a more supervised care setting.

References

1. Louis DN, Suva ML, Burger PC et al. Chapter 1: Diffuse astrocytoma and oligoendendroglial tumors – Glioblastoma, IDH wildtype. In: Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: International Agency for Research on Cancer; 2016: 28-45.
2. Preusser M, de Ribaupierre S, Wohrer A, et al. Current concepts and management of glioblastoma. Ann Neurol. 2011; 70(1): 9-21.
3. Strupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of EORTC-NCIC trial. Lancet Oncol. 2009; 10(5): 459-66.
4. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013; 310(17): 1842-50.
5. Boele FW, Rooney AG, Grant R, Klein M. Psychiatric symptoms in glioma patients: from diagnosis to management. Neuropsychiatr Dis Treat. 2015; 11: 1413-20.
6. Fritz L, Dirven L, Reijneveld JC, et al. Advance care planning in glioblastoma patients. Cancers (Basel). 2016; 8(11): E 102.
7. Cetin OE, Isler C, Uzan M, Ozkara C. Epilepsy-related brain tumors. Seizure. 2017; 44: 93-97.
8. Franceschi E, Minichillo S, Brandes AA. Pharmacotherapy of glioblastoma: established treatments and emerging concepts. CNS Drugs. 2017; 31(8): 675-684.
9. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevecizumab for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8): 699-708.
10. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8): 709-22.
11. Kesselheim JC, Norden AD, Wen PY, Joffe S. Discontinuing bevacizumab in patients with glioblastoma: an ethical analysis. Oncologist. 2011; 16(10): 1435-9.
12. Mehta M, Wen P, Nishikawa R, Reardon D, Peters K. Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Review Oncol Hematol. 2017; 111: 60-65.
13. Kuchinad KE, Strowd R, Evans A, Riley WA, Smith TJ. End of life care for glioblastoma patients at a large academic care center. J Neurooncol. 2017; 134(1): 75-81.
14. Thier K, Calabek B, Tinchon A, et al. The last 10 days of patients with glioblastoma: assessment of clinical signs and symptoms as well as treatment. Am J Hosp Palliat Care. 2016; 33(10): 985-988.
15. Valko PO, Siddique A, Linsenmeier C, et al.  Prevalence and predictors of fatigue in glioblastoma: a prospective study.  Neuro Oncol 2015;17(2):274-281. 

Conflicts of Interest: None

Author Affiliations: University of Minnesota Medical School, Minneapolis, MN (RP, EN, SM), Hennepin County Medical Center, Minneapolis, MN (SM).

Version History: Originally edited by Sean Marks MD; first electronically published in February 2018