Researchers and Advocates Work Together to Advance Glioblastoma Understanding and Treatment

During the spring of 2008, Edward Kennedy, the U.S. senator from Massachusetts, was diagnosed with a particularly aggressive form of brain cancer known as glioblastoma multiforme (GBM). Approximately 15 months after diagnosis, and following standard treatment consisting of surgery, radiation and chemotherapy, Kennedy died from the disease.

Close to half a decade after Senator Kennedy's death, interest has grown in the treatment of this disease. In an effort to improve outcomes for those with GBM, the National Brain Tumor Society (NTBS), a clearinghouse for information about brain cancers, has launched its "Defeat GBM Research Collaborative." This initiative is a multi-site research effort with a goal of doubling the five-year survival rate of GBM patients. To do this, the NBTS has created a network of brain tumor researchers in cancer institutions from around the world to collaboratively conduct focused research. These investigator teams, in turn, are being overseen by a group of brain cancer experts forming the Strategic Scientific Advisory Council.

[Patients and survivors connect on Twitter with #BTSM]

Improving outcomes for those diagnosed with GBM is important both to the NBTS and the specialists who diagnose and treat this disease. Patients with GBM have a median survival of fewer than 15 months and the five-year survival rate is less than 5 percent. The NTBS also classifies GBM as "the most common and deadliest of malignant primary brain tumors in adults."

The good news in GBM research is that imaging technologies developed during the latter part of the 20th century have helped researchers, clinicians and doctors better diagnose the disease.

This type of brain cancer also has debilitative secondary impacts as well such as physical degeneration, loss of speech and motor skills. Adding to the issue is that it isn't readily diagnosed at an early and more curable stage. Often, by the time patients see a physician for blinding headaches, seizures, or loss of motor skills, cancer has already gained a solid foothold in the brain.

GBM is classified as primary or secondary. Primary glioblastomas are referred to as de novo—in other words, they develop quickly without any clinical evidence of a pre-existing, less cancerous lesion. This primary brain cancer, which is often diagnosed among older patients, accounts for approximately 60 percent of all GBM cases.

Secondary glioblastomas typically develop as a malignant progression from a low-grade astrocytoma and is found mostly in patients younger than 45 years of age. Astrocytomas are tumors that develop from astrocytes, which are, in turn, the tissues that support the brain. In addition to having different pathologies, primary and secondary GBMs differ in that the latter has a better prognosis for the length of survival time.

[Read "Who's to blame for lack of brain cancer awareness?" by Liz Salmi]

The good news in GBM research is that imaging technologies developed during the latter part of the 20th century have helped researchers, clinicians and doctors better diagnosis the disease. As such, "we've been able to diagnose this disease before the patient comes, in extremis, to the hospital," says Santosh Kesari, director of the Translational Neuro-oncology Laboratories at the University of California, San Diego, Moores Cancer Center.

The challenge, however, remains in treating GBM. "Even with all the improvements in cancer, in general, during the past three or four decades, we've only been able to make little impact on GBM," Kesari says.

GBM is dubbed a "glioma," in other words, a tumor arising from the glial cells that protect neurons in the brain and support nerve cells. Though the explanation behind GBM is fairly straightforward, its causes, manifestations, and treatment are not.

The disease is called "multiforme" for a reason, namely it has a lot of different parts. "When you look under the microscope at this cancer, you see multiple forms," says Andrew Parsa, chair of the Department of Neurological Surgery at Northwestern Memorial Hospital in Chicago. "It's not a homogeneous picture. There are elements of necrosis, of proliferation, of angiogenesis and invasion." The good news, however, is that "each of these elements represents an avenue for possible targeting through novel therapies," he says.

[Read "Defeating glioblastoma multiforme will take full-force effort" by W.K. Alfred Yung]

The star-shaped formation of the glial is another reason why GBM is so difficult to treat. "This is an invasive cancer, meaning it has tentacles reaching into the normal structures of the brain," Kesari points out. "Even the best surgical hands can't get those microscopic cancer cells out."

Then there is the fact that GBM is, well, brain cancer. "Because it's the brain, you can't remove the cancer totally," notes Manmeet Ahluwalia, staff physician at the Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center at the Cleveland Clinic in Ohio. "If you try, depending on the location of the tumor, the patient can lose critical neurological function, for example, motor skills or it can impact speech."

Adding to the issue is that there are four genetic subtypes associated with GBM, the presence of which may dictate how an individual will respond to different therapies; another reason why treatment is challenging. The four gene mutations are NF1 (identified as the cause of neurofibromatosis, a rare, inherited disorder characterized by uncontrolled tissue growth along nerves); ERBB2 (also known as HER2 and typically associated with breast cancer); TP53 (a gene found in many types of cancers) and PIK3R1 (which controls enzymes found in many types of cancers). As such, a drug that might target one subtype or part of a tumor might not target another.

Then there is the aspect known as the blood-brain barrier. "The brain has a natural defense to prevent toxins from getting in," Kesari says. "It also makes it difficult to get therapeutic drugs in there as well."

Finally, there is the fact that, unlike lung cancer and breast cancer, GBM impacts only a small percentage of patients. Though Kennedy's GBM attracted attention, "It's a fairly uncommon cancer," Ahluwalia says. "We might see around 10,000 cases in the U.S. every year. That's small, compared to the 200,000 cases we see of breast cancer and lung cancer."

Because the market is small, few pharmaceutical companies are delving into ways to treat or prevent GBM. "There's been very little drug development in this area," Kesari says. "Though the standard of care for this disease is better than even a decade ago, the survival rate is still poor."

Further complicating the issue is that there is no apparent cause for the disease, although the NBTS indicates research increasingly points to the fact that genetic mutations might be at the root of this issue. As such, much of the GBM research and clinical trials are focused on genetic mutations.

Glioblastoma multiforme treatment is threefold: Surgery, radiation and chemotherapy.

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Drugs typically used include the oral chemotherapy agent Temodar (temozolomide) or Avastin (bevacizumab), an angiogenesis inhibitor used to slow the growth of blood vessels to the tumor. Sometimes, in an attempt to circumvent the blood-brain barrier, a treatment called Gliadel (prolifeprosan 20 with a carmustine implant), is used. Gliadel consists of a wafer containing an alkylating chemotherapy agent that is surgically implanted in the patient's brain following surgical removal of the tumor. The Gliadel wafer delivers the drug directly to the tumor site to kill any remaining cancerous cells.

Unfortunately, even with this treatment, most patients with GBM follow the same course experienced by Kennedy—they die within two years of their diagnoses. With such a sobering outlook in GBM, current research into the disease may help turn the corner in survival.

In addition to the NBTS' research collaborative, many cancer centers throughout the U.S. are researching different therapies to treat GBM. Northwestern Medicine, for example, recently joined a second-phase clinical trial in conjunction with the National Cancer Institute investigating whether a vaccine made from a patient's own brain tumor could slow the growth of that tumor and promote the patient's survival. Although the national trial was first announced in April 2013, Parsa, who is chairing the trial at Northwestern, helped launch the area of vaccine research in 2006 while at the University of California, San Francisco; the results from that research demonstrated the vaccine extended survival rates compared with standard therapies. This second phase will determine if the vaccine is more effective when given with Avastin. In this study, more than 200 patients with recurrent glioblastoma that can be surgically removed are being enrolled.

Meanwhile, at UC San Diego Moores Cancer Center, tumor profile research is ongoing. "One of the issues we explore in terms of drug development is to individualize therapy by obtaining cells from each patient's tumor at the time of surgery and grow them in the lab," Kesari says. "We call this a living tissue bank. We can figure out which mutations each patient's tumor has, and match [the] best drugs for that particular patient."

The hope with the tissue bank, he says, is to take results from the laboratory and understand what treatments the patients’ cancers will respond to, thus helping to personalize treatment in the future. "There is also a great need to develop new brain cancer specific drugs, which we and others are working on," he adds.

Such research also focuses on specific genetic mutations. Ahuwali, for example, points out that patients with tumors exhibiting mutations of the IDH1 gene (isocitrate dehydrogenase 1) tend to survive longer. Research recently published in the New England Journal of Medicine backs this up. The research, involving the extraction of DNA from samples of primary brain tumor and xenografts from blood and tissue banks, showed that patients with the IDH1 and IDH2 mutations do tend to have longer survival. The researchers point out that, for example, IDH mutation tests can help separate different types of astrocytomas causing the disease. A more accurate diagnosis can lead to more targeted treatments, which would, in turn, yield better outcomes.

At the Cleveland Clinic's Burkhardt Brain Tumor & NeuroOncology Center, trials are underway for use of NovoTTF-100A, a device that delivers a low frequency of electromagnetic waves targeted at specific cell components and allowing them to divide. This therapy is being tested with Avastin in patients with recurrent glioblastoma in a multicenter trial developed by Ahluwalia. Though the NovoTTF-100A can be active against GBM and has been approved by the U.S. Food and Drug Administration (FDA), the jury is still out as to its effectiveness in treating GBM relative to other therapies. One study compared the device with chemotherapy and found that, while there was little improvement in the survival rate, quality of life improved and toxicity from chemotherapy agents was reduced.

Ahuwalia is also excited about the use of MRI-guided laser interstitial thermal therapy (LITT) in treating these tumors and says the Cleveland Clinic, in conjunction with other hospitals throughout the U.S. and Canada, is in the process of conducting a randomized trial to evaluate the impact of this technology.

Given the relatively small population suffering from this disease, and given the relatively few FDA-approved therapies out there, many experts recommend patients look into clinical trials at reputable cancer centers. Parsa believes patients participating in such trials are likely to receive more attention, given the focus of such trials is to improve outcomes among those with GBM. Furthermore, "they can participate in cutting-edge therapies" Parsa adds.

Though survival rates from GBM are still low, and drugs and treatments are still in research phases, Parsa is heartened by what's happening in the field of research. As there is no cure for GBM, the goal, he says, is to try to move GBM toward a chronic disease that can be managed.

"Getting to a chronic state is like climbing a mountain," he explains. "You climb a certain height, set up a base camp and regroup before going further. These incremental steps are base camps."