The questioning of former FBI director James B. Comey by Sen. John McCain (R-Ariz.) during a June 8 Senate Intelligence Committee hearing raised more than a few eyebrows; Sen. McCain seemed confused and disoriented, at one point referring to Mr. Comey as “President Comey,” but a possible medical explanation emerged soon after.
On July 14, Sen. McCain, 80, underwent surgery to remove a 5-cm blood clot that had been discovered above his left eye during a physical, and on July 19, the Mayo Clinic in Phoenix, where he had undergone the procedure, announced at his request that, “subsequent tissue pathology revealed that a primary brain tumor known as a glioblastoma was associated with the blood clot.”
Glioblastoma features
While Sen. McCain’s symptoms can’t necessarily be attributed to the glioblastoma, it is not unusual for glioblastoma patients to present with some sort of neurologic deficit, such as speech issues, unilateral weakness, or confusion, according to Eudocia Quant Lee, MD , a neuro-oncologist at Dana-Farber Cancer Institute, Boston.
“Most people [with a glioblastoma] do have some sort of sign or symptom that leads to brain imaging that identifies the mass,” she said in an interview.
Neuro-oncologist Manmeet Singh Ahluwalia, MD , of the Cleveland Clinic said seizures, persistent headaches, double or blurred vision, and changes in ability to think and learn can also be presenting symptoms.
Glioblastoma is the most common malignant primary brain tumor diagnosed in adults, with an estimated 12,000-13,000 new cases occurring each year in the United States. It is more common among older adults but can occur in younger patients. It arises in the brain and generally stays within the central nervous system, Dr. Lee explained, noting that it is much less common than lung cancer, breast cancer, and melanoma.
“It doesn’t usually metastasize. That being said, prognosis is unfortunately limited,” she said.
This is particularly true for older patients.
Prognosis and age
“We know, in general – as with most cancers – that the older you’re diagnosed with your cancer, the poorer your prognosis is,” she said, adding that other health issues and the ability to tolerate treatment can affect outcomes.
Outcomes also can be affected by type of surgery, functional status, extent of treatment, and molecular subtypes of the glioblastoma, Dr. Ahluwalia said.
Survival generally ranges about 14-18 months, although about 10% of patients live 5 years or longer.
A study presented in June at the annual meeting of the American Society of Clinical Oncology (ASCO) reaffirmed that the long-term survival (LTS) rate among elderly patients with glioblastoma is poor. Of 2,071 patients enrolled in the German Glioma Network database during 2004-2012, 425 with histologic confirmation of glioblastoma were aged 71 years or older and, of those, only 27 (6.4%) survived at least 2 years (median, 37.1 months).
The study, presented in a poster by Michael Weller, MD , of University Hospital and University of Zürich and his colleagues, also showed that, compared with the 398 older patients who survived less than 2 years (median, 6.2 months), those who survived longer had “more intensive up-front treatment and a trend toward higher initial Karnofsky performance scores as distinguishing clinical factors.”
In addition, molecular analyses showed more frequent O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in those with longer survival, while isocitrate dehydrogenase (IDH) mutations were restricted to single patients.
“Collectively, our findings confirm that LTS is rare in elderly patients with glioblastoma and that clinical and tumor-associated molecular factors linked to LTS resemble those in standard-age patients, except for less common IDH mutation,” the investigators wrote.
Another abstract published online in conjunction with the ASCO annual meeting looked at outcomes, based on age and MGMT analysis, and similarly found that aggressive treatment with chemoradiation is associated with better outcomes in both younger and older patients.
In that study by Suryanarayan Mohapatra, MD, of Cleveland Clinic–Fairview Hospital, and his colleagues – including Dr. Ahluwalia – 567 of 1,165 patients were aged 65 years or older. The benefits of chemoradiation therapy, which was associated with a significantly lower risk of death vs. radiation therapy alone in the study, were more pronounced among the older patients (hazard ratio, 0.45 vs. 0.61 for those under age 65 years), but the difference did not reach statistical significance.
Dr. Mohapatra and his colleagues also showed that more aggressive therapy resulted in better overall and progression-free survival regardless of MGMT methylation status, but that there was no difference between the age groups on this measure. Overall and progression-free survival also were significantly better with gross-total resection and subtotal resection vs. biopsy only, and with diagnosis during 2009 and later vs. during 2007-2008. However, a difference between the two age groups was seen with respect to overall survival only among those diagnosed during 2009 or later, with a more prominent impact among the younger group, the investigators reported.
“Older individuals often get less aggressive treatment. However, based on the research, active and functional older patients should get aggressive treatment,” Dr. Ahluwalia said. “We advocate tailor-made treatment that takes into account patient condition, location of tumor, functional status, etc., in addition to patient age.”
Standard treatment approaches
The first step in the treatment of glioblastomas is maximal safe therapy, Dr. Lee said.
“You want to achieve as much of a resection as possible without leaving the patient with some sort of permanent neurologic deficit that could severely compromise the quality of their life,” she explained.
Sen. McCain’s tumor was “completely resected by imaging criteria,” according to the Mayo Clinic statement, which also noted that treatment options might include a combination of chemotherapy and radiation.
Indeed, the standard of care for glioblastomas after surgery is combined chemotherapy and radiation – typically given as approximately 6 weeks of radiation combined with oral temozolomide chemotherapy – followed by 6 monthly cycles of temozolomide, she explained.
Radiation is sometimes given for only 3 weeks, but this option is mainly reserved for elderly patients, she said, adding that trials in patients aged 65-70 years have shown that this shorter course of radiation can be equally effective but potentially less toxic.
Emerging treatment approaches
Another treatment that has shown promise involves the use of tumor-treating fields (TTFields) – a locoregionally delivered antimitotic treatment that disrupts cell division and organelle assembly.
A 2015 phase 3 trial showed that adding TTFields to maintenance temozolomide significantly prolonged progression-free and overall survival, Dr. Ahluwalia said.
Other studies, including two presented during poster sessions at the ASCO annual meeting, have shown a progression-free survival benefit with the addition of bevacizumab to the treatment regimen. One open-label phase 2 study showed that hypofractionated radiotherapy in combination with IV bevacizumab every 2 weeks vs. radiotherapy alone in newly diagnosed patients over age 65 years improved progression-free survival (median, 7.6 vs. 4.8 months), but not overall survival (median, 12.1 vs. 12.2 months).
Another phase 2 study presented by Phioanh (Leia) Nghiemphu, MD , of the University of California, Los Angeles, showed that in newly diagnosed patients aged 70 years and older, upfront treatment with bevacizumab and temozolomide was associated with promising survival benefits (overall survival, 12.3 months; progression-free survival, 5.1 months) and tolerable side effects. The best survival in multivariate analysis was in patients who received radiotherapy at progression; it was unclear whether the addition of bevacizumab led to a survival advantage, but it may have allowed delay of radiotherapy treatment, she noted.
“Although we have no cure for glioblastoma, treatments can control tumor growth for a period of time, and there are additional promising therapies emerging every day to treat this deadly cancer, she said in an interview. “There has been increasing interest in developing better therapies for the older patients with glioblastoma with less toxicity and still-robust survival, such as the addition of bevacizumab or a short course of radiotherapy with temozolomide chemotherapy.”
Dr. Ahluwalia encourages clinical trial participation for patients diagnosed with glioblastoma and noted that he is particularly excited about immunotherapy and targeted therapy trials.
Dr. Lee has served as consultant to Eli Lilly. Dr. Ahluwalia disclosed a financial relationship with multiple companies, including Novocure, which markets a TTFields device. Dr. Weller disclosed a financial relationships with multiple companies, including Novocure; Merck Sharp & Dohme, which markets temozolomide; and Roche, which markets bevacizumab. Dr. Nghiemphu has received research funding from Genentech/Roche and Novartis. Dr. Mohapatra reporting having no disclosures.
