From OncoLog, June 2013, Vol. 58, No. 6

Addressing Emerging Survivorship Issues in Glioblastoma Patients

By Joe Munch

An increasing number of glioblastoma patients are becoming “long-term” survivors—living 3 or more years after diagnosis.

But this small success is bittersweet: these patients’ prolonged survival can be marred by the lasting effects of the tumor and its treatments. As the concept of survivorship in this population emerges, researchers are working to identify and address the issues facing glioblastoma patients during and after treatment.

By the numbers

Since the U.S. Food and Drug Administration’s approval of temozolomide for the treatment of adult patients with newly diagnosed glioblastoma in 2005, the 2-year survival rate of glioblastoma patients has doubled, from 12% to about 25%.

“Ten years ago, people were not talking about brain tumor survivorship issues,” said John de Groot, M.D., an associate professor in the Department of Neuro-Oncology at The University of Texas MD Anderson Cancer Center. “But this new standard of care seems to have shifted the bar.”

Despite this progress, nearly 100% of glioblastomas recur, usually within 6–8 months. The median survival duration of glioblastoma patients is 16–19 months; their 5-year survival rate is around 10%.

“There’s a sense of futility if you read the numbers. But statistics are just statistics; they mean nothing for the individual patient,” Terri Armstrong, Ph.D., a professor and an advanced practice nurse in the Department of Neuro-Oncology, said. “Our approach to every glioblastoma patient is to control the tumor for as long as we can. It’s something the person is going to be dealing with for the rest of his or her life, and our goal is to maximize the patient’s treatment options and ability to function during that time.”

Lasting tumor effects

Symptoms of glioblastoma, the most common type of brain cancer, include headaches, seizures, changes in personality, and focal weakness on one side of the body. Many glioblastoma patients also experience tumor-induced cognitive deficits—primarily memory loss and loss of executive function—that may persist or worsen through therapy. Glioblastoma patients also experience mood disorders and personality changes at rates that are substantially higher than those of the general population of cancer patients.

“This disease ravages the organ that supports our ability to think, our personality, and our ability to modulate our emotions and behavior—all of which define who we are and determine how we navigate our world,” said Jeffrey Wefel, Ph.D., an associate professor in the Department of Neuro-Oncology.

As with any brain tumor, the symptoms of glioblastoma—especially cognitive deficits—depend largely on the location of the tumor. Problems with executive function, for example, are more common in patients with tumors in the frontal lobe. Cognitive processes that rely on widely distributed neural networks, such as learning and memory, are affected by tumors in various locations.

The deficits created by glioblastoma can sometimes be permanent because the tumor destroys a portion of the brain. The technology to rebuild portions of the brain is not yet available for clinical use, and researchers are still working to develop treatments that will harness the brain’s neuroplasticity to rebuild function in neighboring areas. As a result, glioblastomas are often treated much like a neurodegenerative condition: cognitive interventions focus on the patient’s residual strengths and use a variety of cognitive prosthetics—assistive technologies designed to help improve the patient’s daily function—to minimize the impact of the cognitive deficit.

“Oftentimes, we do not expect to see a dramatic restoration of the impaired cognitive process, but we help patients compensate so they can maintain as much independence as possible for as long as possible to help them enhance or maintain their quality of life,” Dr. Wefel said.

Dr. Wefel is the interim chief of MD Anderson’s Neuropsychology Section, a team of neuropsychologists who provide care and recommendations alongside neurosurgeons, radiation oncologists, and medical oncologists. These neuropsychologists regularly assess glioblastoma patients before, during, and after treatment to identify and address changes in cognitive function, behavior, and mood.

“By monitoring patients over time, we can identify changes in cognitive function or behavior that may be early indicators of tumor growth. Based on those findings, physicians may consider changing therapy, monitoring the patient more closely, or offering intervention strategies and referrals for other supportive care needs,” Dr. Wefel said.

According to Dr. Armstrong, experience is key in caring for this population. “One of the issues patients often say they have before they come here is that they feel very isolated. In their community, they may be seeing a doctor who has seen one other glioblastoma patient before. But here, that’s all we do. Many of us see 20 or 30 patients with this disease each week,” she said. “I think patients also feel comforted that there are other people here who are like them—connections are being made in their support groups or in the waiting room.”

Effects of treatment

In addition to having to contend with the adverse effects of the tumor itself, glioblastoma patients receive a number of therapies that also place healthy brain tissue at risk. The standard treatment for glioblastoma patients is surgery to remove as much of the tumor as possible followed by concurrent temozolomide and radiation therapy and adjuvant temozolomide.

“These therapies are all directed at the brain, but they have very little ability to target just cancer cells. They also will affect the healthy tissue,” Dr. Wefel said.

Surgery, though it has not been shown definitively to improve survival outcomes over chemoradiation with temozolomide, benefits patients by relieving the mass effect of the tumor. However, surgery often requires the transection of normal brain tissue to obtain clear surgical margins, which can result in further cognitive or neurological deficits.

Radiation therapy, by far the most effective treatment against glioblastoma, can cause permanent hair loss and short-term fatigue; over time, it can increase patients’ risk for secondary tumors and result in additional cognitive and neurological impairments.

Temozolomide, despite the survival benefit it has shown, nevertheless increases patients’ risk of infection and can cause fatigue, nausea, or vomiting. In fact, temozolomide may increase the neurotoxicity of radiation.

“We think that temozolomide may work in part by being a radiation sensitizer—making the radiation more effective—and that’s great in terms of destroying the tumor, but then you’re left with the side effects of radiation to the brain,” Dr. de Groot said.

Glioblastoma patients who receive bevacizumab for recurrent disease may experience high blood pressure, be at a higher risk for stroke, and have blood-related issues such as hemorrhaging, clotting, and wound-healing complications.

The effects of glioblastoma and its treatments can also give rise to a number of physical, functional, and social issues that affect patients’ quality of life. For example, only 20%–30% of patients return to a competitive work environment, usually with accommodations or a reduced role.

A number of intervention approaches, many in their infancy, are aimed at helping glioblastoma patients cope with the fallout of the disease and its treatments. For example, Dr. Wefel is conducting a feasibility study of a computerized neuroplasticity-based cognitive exercise program for improving patients’ cognition. “We’re very excited about it,” Dr. Wefel said. “Traditional neuropsychological rehabilitation frequently requires daily sessions for several weeks or months—and for many of our patients, coming to MD Anderson that often just isn’t possible.”

Other interventions aim to address the roots of specific issues. Many glioblastoma patients experience seizures even after the tumor has been removed; rather than addressing the aftermath of the seizures, Dr. Armstrong and her colleagues are investigating whether prophylactic anticonvulsants can prevent or delay the occurrence of seizures.

Dr. Armstrong’s team also found that patients who received a high dose of radiation to the pineal gland had high levels of melatonin—a hormone that helps regulate the sleep-wake cycle—during the day, resulting in fatigue. In response to these findings, the group plans to explore methods of regulating melatonin to prevent fatigue.

“We’re trying to take a step back and look at the biology underlying the fatigue,” Dr. Armstrong said. “Instead of just giving patients something to deal with the fatigue, we hope to prevent the fatigue from occurring in the first place.”

Focusing on survival

Even as the concept of glioblastoma survivorship emerges, the focus remains on extending patients’ lives by adjusting existing therapies and identifying new approaches to combat the disease. For example, radiation oncologists are developing methods to more effectively limit the amount of radiation to normal brain tissue. These methods include proton therapy, which theoretically can be more accurately delivered to the tumor and spare normal brain tissue.

Clinical trials in glioblastoma are investigating the use of agents that have shown promise against other cancers or other diseases. For example, the addition of vorinostat (used to treat cutaneous T-cell lymphoma) to bevacizumab is being tested in patients with glioblastoma, as is the addition of memantine, mefloquine, and metformin (used to treat Alzheimer disease, malaria, and type 2 diabetes, respectively) to adjuvant temozolomide. Other glioblastoma trials are investigating the potential of novel agents and nontraditional therapies such as replication-competent adenovirus (Delta-24-RGD).

Data from projects such as The Cancer Genome Atlas are driving additional avenues of glioblastoma research. With these data, researchers hope to identify biomarkers that can be used to determine which patients will benefit from specific treatments.

“I think that people who have been treating this disease for 30 years definitely see this time as the initial stage of a new era,” Dr. de Groot said. “A lot of people are thinking that we’re on the verge of a breakthrough that sets us in motion to really improve the survival of patients with glioblastoma.”

Glioblastoma in Children

A rare disease in adults, glioblastoma is even rarer in children, though the disease is handled in much the same way in both populations. Pediatric glioblastoma patients receive the same treatment as adult glioblastoma patients—surgery, with complete resection if possible, followed by radiation therapy and chemotherapy—and the survival rates of the two populations are similarly poor. However, pediatric patients are much more susceptible than adult patients to the adverse cognitive effects of radiation therapy.

Although teenagers tend to tolerate radiation therapy to the brain with cognitive effects similar to those of adults, younger children suffer more cognitive loss because their brains are not fully developed.

“The younger the brain is, the more adverse effects you see from radiation,” said Michael Rytting, M.D., a professor in the Department of Pediatrics. “It used to be a hard-and-fast rule that if a child less than 3 years of age received treatment for a brain tumor, you would do anything you could not to use radiation because it would devastate the brain.”

Today, however, many pediatric glioblastoma patients are referred to MD Anderson to receive proton therapy, especially when surgery and chemotherapy have not been successful.

“We’ve started to give younger children with glioblastomas and other aggressive brain tumors more treatment with radiation now that we can use protons,” Dr. Rytting said. “The thought is that proton therapy is more directed with less damage to surrounding tissue, so hopefully you’re not affecting as much of the normal brain; but we don’t yet know definitively.”

Radiation-induced hormonal deficiencies are also common but treatable. For example, growth hormone therapy may be necessary to prevent significant loss of stature for patients in whom radiation has damaged the pituitary gland. Testosterone or thyroid hormone replacement therapies are often necessary for patients in whom radiation has halted the production of these hormones.

“The big issues in long-term pediatric glioblastoma survivors are hormonal deficiencies and the secondary malignancies that can happen because of radiation, including myelodysplastic syndrome and acute myeloid leukemia,” Dr. Rytting said. “These things also occur in adults, but the length of time they have for these things to develop is quite a bit shorter.”

Another less devastating concern stemming from radiation therapy is hair loss. Although chemotherapy is well known to cause temporary hair loss, some patients do not realize that radiation delivered to the scalp can cause permanent hair loss.

“Even at smaller doses, patients can have very thin hair, and that can really bother them,” Dr. Rytting said. “When they get a high radiation dose focally, they get areas where the hair just doesn’t grow back very well. This isn’t such a big deal when you’re 50, but it can be when you’re 15.”

For more information, call Dr. Michael Rytting at 713-792-4855.

For more information, call Dr. Terri Armstrong at 713-745-4621, Dr. John de Groot at 713-745-3072, or Dr. Jeffrey Wefel at 713-563-0514.


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