About two weeks ago, Senator John McCain’s office disclosed that the 80-year-old politician from Arizona had been diagnosed with an aggressive brain tumor called glioblastoma. Senator McCain joins the tens of thousands of Americans who are diagnosed with this cancer every year, and he’s not the only prominent politician to ever fall victim to the disease. Massachusetts senator Ted Kennedy died after only a 15 month battle with the disease in 2009 and Beau Biden, son of former Vice President Joe Biden, died of the same cancer in 2015. But what is a glioblastoma, and how is it managed? In this week’s episode of BrainWaves, Drs. Neena Cherayil and Amy Pruitt summarize what doctors and patients need to know about this terrifying disease.
Any cancer diagnosis can be devastating, but malignant CNS tumors such as glioblastoma multiforme (GBM) carry an alarmingly poor prognosis. The median survival for the disease is about one year, and less than 10% of GBM patients survive 2 years from time of diagnosis, making it one of the deadliest solid cancers today. Despite the striking statistics, there is more hope than ever for potential treatments as basic science and clinical research uncovers specific gene signatures of each tumor leading to more targeted and personalized treatment options.
Glioblastoma usually occurs sporadically and can strike at any age though the vast majority of patients are over age 40 with a peak incidence between 60 – 75 years of age. GBM patients can first come to medical attention in a variety of ways, typically with insidious onset and progression of headaches, altered mental status, syncope, seizures, or other focal neurologic signs related to the location of the tumor. Indeed, Senator McCain was noted to have somewhat confused lines of questioning during the hearings of former FBI director James Comey back in June. At an annual check-up, he complained to his doctor of feeling cognitively foggy with intermittent double vision prompting a head CT.
Glioblastomas typically arise above the tentorium in the cerebral hemispheres and appear as a well-circumscribed hypercellular mass with associated vasogenic edema on head imaging. These masses can often cross the midline via the corpus callosum, giving it a winged appearance termed a “butterfly glioma”.
Among primary tumors of the central nervous system, glioblastoma is a high grade glioma. Gliomas were previously grouped according to cell lineage and a “grade” based on histopathologic appearance — that is, how abnormal the cells appear under the microscope. Tumors that are more cellular, rapidly dividing, with more atypical nuclei are often “higher grade”. Much of the older World Health Organization classification that grouped gliomas into low grade slowly growing or high grade rapidly progressive tumors are going out the window as molecular markers revolutionize how we think about the growth pattern and even treatment options for tumors.
Glioblastomas can be primary, arising de novo from glial cells, or secondary, arising out of other “lower grade” glial tumors. Primary GBMs, like that diagnosed in Senator McCain, account for 80% of glioblastomas and occur in older patients. The IDH status is a crucial branch point in this classification of GBM. IDH1 and 2, or isocitrate dehydrogenase, is an enzyme present throughout all glial cells. Mutations in IDH lead to overproduction of a metabolite that inhibits tumor-promoting gene regulation enzymes which activate oncogenes or inactivate tumor suppressor genes. IDH mutated tumors have a “less malignant” phenotype – most often occurring in the frontal lobes with decreased necrosis and vascularity than their normal or wildtype IDH counterparts. IDH mutant GBMs also tend to occur in younger adults with a mean age of 45 years and often co-occur with other favorable genetic mutations. As a result, IDH mutations are associated with a significantly improved prognosis, a nearly doubled median survival rate, compared to tumors with wild type IDH. Unfortunately, the overwhelming majority or approximately 90% of glioblastomas are IDH-WT.
MGMT promoter methylation is another marker common in secondary glioblastomas that has significant treatment implications. MGMT is a DNA repair protein that removes alkyl groups from DNA, making cells resistant to an alkylating agent like temozolamide (TMZ)- the first line adjuvant chemotherapy agent for patients with glioblastoma. TMZ acts by alkylating DNA in cells thereby causing cellular death. Tumors that have methylation of the MGMT promoter silence the production of this DNA repair protein, increasing temozolamide sensitivity. Approximately 50% of newly diagnosed GBMs have a methylated MGMT promoter. Unsurprisingly, it is associated with better response to TMZ but also improves radiosensitization, improving progression free survival and overall survival in combined treatment approach. Regardless of treatment choice, MGMT promoter methylation has prognostic and predictive significance in patients with GBM with better overall survival. IDH mutated subtypes are more likely to have increased MGMT promoter methylation.
The initial treatment regimen for any patient with glioblastoma consists of safest maximal surgical resection followed by local radiation and concurrent maintenance chemotherapy with the aforementioned temozolamide for 6 or 12 cycles. Aka, the “Stupp” regimen, which has been shown to improve 2 year survival from 10.4% for radiation alone to 26.5% with combined chemoradiation. The regimen is overall fairly well-tolerated with minimal side effects as discussed in the podcast.
Patients are followed incredibly closely following completion of therapy with MRI imaging every 3 months or sooner depending on the patient. It is often difficult to distinguish effects of concurrent chemoradiation from that of true malignant progression. When there is an expected response to radiation therapy with slight worsening of symptoms and fatigue and an interval increase in the amount of vasogenic edema or enhancement early in the course of treatment, “pseudoprogression” should be suspected. Pseudoprogression can appear as contrast enhancement in the tumor bed or an increase in lesion size (right). It typically occurs in the first 3 months after combination chemoradiation but has been known to occur as early as a few weeks after therapy up to 6 months. It is likely an exaggerated response to therapy and can be managed with steroids.
Due to microscopically infiltrative nature of GBM cells, most patients will ultimately go on to have true progression. Repeat therapy may include repeat surgery, radiosurgery, or TMZ challenge or addition of newer antiangiogenic agents (such as bevacizumab) or other chemotherapies, all of which is discussed in greater detail within the podcast. But these regimens are not thought to improve survival. The aim of these therapies is primarily to improve overall quality of life via alleviation of neurologic symptoms (seizures, for example) as there is no survival benefit with any of these regimens. Median survival from time of recurrence is approximately 5-7 months.
The numbers are bleak, but the future is still bright. Indeed, we have made dramatic strides in the management of GBM in the last decade including molecular biomarkers lending key prognostic information and progress in the area of imaging, surgical, and chemotherapeutic management of this disease. Advances in understanding GBM biology are and will continue to be central to developing more effective treatments including gene or immunotherapy.
BrainWaves podcasts and online content are intended for medical education purposes only. This is not a comprehensive review on glioblastoma, nor should you use it when you are managing patients who suffer from this disease.
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