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From OncoLog, March 2011, Vol. 56, No. 3

Glioblastoma Cure Remains Elusive Despite Treatment Advances

By Bryan Tutt

Aggressive surgery followed by radiation therapy and chemotherapy offers hope of long-term survival for some patients with glioblastoma, but for most glioblastoma patients, the prognosis is poor.

Twelve to fourteen thousand new cases of glioblastoma multiforme are diagnosed in the United States each year, and less than 10% of newly diagnosed glioblastoma patients survive 5 years. “Glioblastoma is a somewhat rare cancer, but it contributes to a large number of lost years of life because it hits people in their prime—their 30s, 40s, and 50s,” said John de Groot, M.D., an associate professor in the Department of Neuro-Oncology at The University of Texas MD Anderson Cancer Center.

Brain tumors usually are detected by computed tomography or magnetic resonance imaging (MRI) after patients present with symptoms, but the final diagnosis of glioblastoma is not made until after the tumor is removed surgically and examined pathologically.

Surgery

Surgical resection, which requires a craniotomy, is almost always the first stage of treatment for patients with suspected glioblastomas. Because glioblastomas typically have cells that extend like thin tendrils several centimeters into the surrounding brain tissue, the entire tumor cannot be removed. However, surgery usually alleviates symptoms and can extend patients’ survival.

“Most of the time, we recommend the most aggressive surgery possible,” said Dr. de Groot. “If you can get out 92%–98% of the tumor, you can prolong patient survival.” One of the most cited articles on this subject was published in the Journal of Neurosurgery by MD Anderson surgeons in 2001. This retrospective study of more than 400 patients with glioblastoma showed significantly longer survival times for patients in whom 98% or more of the tumor volume was resected than for those with a lesser extent of resection. More recent studies have corroborated those data. Although long-term survivors—those who live 5 years or longer after their diagnosis of glioblastoma—were rare in all studies, all such survivors had undergone very aggressive surgery.

During surgery for glioblastoma, it is standard practice to use stereotactic computer navigation. Before making their first incision, surgeons point an infrared sensor to anatomic landmarks on the patient to register the landmarks on a preoperative MRI scan loaded into a computer-based image guidance system. Surgeons can point the sensor at a structure during surgery to see the location of that structure on the image. “The navigation system helps us localize critical structures and navigate the patient’s head. This allows us to be very precise with our incisions,” said Ganesh Rao, M.D., an assistant professor in the Department of Neurosurgery who performs three or four glioblastoma resections in a typical week.

“The balance we’re trying to strike is to remove as much tumor as we can without causing neurological damage,” Dr. Rao said. In some cases, especially when tumors are located near the speech-generating centers of the brain, the best way to avoid neurological damage is to perform an awake craniotomy. During an awake craniotomy, a neuro-anesthesiologist makes sure the patient is comfortable but still able to interact with the surgeons, who use an electrical probe to stimulate areas of the brain to determine which areas control certain functions.

Another tool used to help surgeons avoid inflicting neurological damage is preoperative functional MRI. The patient is asked to perform a task like saying a word or moving a hand, and the part of the brain responsible for that function will light up on the MRI scan. “We can use that information and avoid those areas during surgery,” Dr. Rao said.

MD Anderson surgeons have developed several tools to stimulate the brain and identify functions even when the patient is under general anesthesia. For example, surgeons can insert electrodes or needles into the major muscle groups of the arms or legs and use a probe during surgery to identify the areas of the brain being stimulated and register those areas in the computer navigation system. Surgeons can also stimulate a part of the brain during surgery to determine its function. “If I stimulate a certain part of the brain and the neurophysiologist tells me the arm is moving, I know this is a critical part of the brain that needs to be avoided during surgery,” Dr. Rao said. “That’s greatly increased the safety of these operations.”

For a subset of patients, however, the stereotactic navigation system is not sufficient. Dr. Rao explained that many tumors take up the contrast dye used in MRI, which makes the difference between normal tissue and abnormal tissue very obvious on MRI and during surgery. But some brain tumors—especially low-grade tumors but also some glioblastomas—do not take up that dye. Although these tumors can still be distinguished from normal brain tissue, the difference in appearance can be subtle, both on MRI and in surgery.

Difficult-to-distinguish tumors are resected in MD Anderson’s operative MRI suite, where MRI performed during the operation can help surgeons find and remove any residual tumor. Another benefit of the suite is that MRI can be performed to recalibrate the stereotactic navigation system during surgery. This recalibration is sometimes necessary because the effects of gravity or spinal fluid loss may cause the brain to shift during surgery, rendering the original image used for the stereotactic navigation system inaccurate.

The disadvantage of intraoperative MRI is the time it adds to the surgery. “A craniotomy for even the simplest tumor can take 2–3 hours,” Dr. Rao said. “With intraoperative MRI, the average goes up to 6 or 7 hours, so we can do at most two operations a day in the MRI suite.”

Following surgery, patients typically are up and walking within 24 hours and released from the hospital 2–3 days later. However, some patients require a longer stay for rehabilitation, which may include speech therapy or physical therapy. “We’ve learned that the brain will recover from an insult,” Dr. Rao said. “If we do our job as surgeons, these patients will recover; it just takes some time.” Patients typically are able to begin chemotherapy and radiation therapy within a few weeks of surgery.

Chemotherapy and radiation therapy

Dr. de Groot said most glioblastoma patients will follow a standard treatment regimen after the tumor is resected. This consists of 6 weeks of external beam radiation 5 times a week plus oral temozolomide daily.

Anita Mahajan, M.D., a professor in the Department of Radiation Oncology, said the area around the original tumor is treated with photons (about 60 Gy) delivered in standard fractions using either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy (IMRT). She said no difference in clinical results has been seen in the two systems, but IMRT is preferred because of the ease in planning. “IMRT gives us more flexibility to conform the dose to the target and to try to spare the other side of the brain, the brainstem, and the optic chiasm,” Dr. Mahajan said.

After the 6 weeks of combined radiation therapy and chemotherapy, patients continue to receive temozolomide daily for 5 consecutive days in 28-day cycles for 1 year. This regimen was established by a 2005 study, conducted in Europe and Canada, in which patients given 6 months of adjuvant treatment with temozolomide plus radiation therapy had more than double the 2-year overall survival rate of those treated with radiation only (27% and 10%, respectively). Even with this improvement, the 5-year overall survival rate for patients with glioblastoma remains low—around 8%.

“The treatment prolongs survival, but it’s not destroying the microscopic extensions of the tumor,” said Dr. de Groot. Unfortunately, most patients will have a recurrence of glioblastoma within 2 years of their original diagnosis. If a patient has a recurrence, a limited number of treatments are available.

“A second surgery is considered for patients with recurrent tumors when there’s a question about the diagnosis or if it can be done very, very easily,” Dr. Mahajan said. A second course of radiation therapy is sometimes given to patients whose cancer recurs in a different area of the brain. However, Dr. Mahajan said, 80% or more of glioblastoma recurrences occur in the same area as the original tumor, precluding additional radiation therapy because of toxicity concerns.

Chemotherapeutic agents may be used to treat recurrent glioblastoma. For example, bevacizumab was approved in May 2009 for the treatment of recurrent glioblastoma, and other agents are available through clinical trials. “Although we go back to square one and think about all our options, the vast majority of our patients whose disease has progressed will be enrolled in a clinical trial,” Dr. Mahajan said.

Ongoing research

New treatments for glioblastoma being developed and tested at MD Anderson include a conditionally replicative adenovirus that kills tumor cells without harming normal brain cells. And XL184, a small-molecule chemotherapeutic drug that inhibits multiple receptor tyrosine kinases, is being studied in several patient groups. Also being studied is a therapeutic vaccine designed to stimulate the immune system to elicit a cytotoxic T cell response against the tumor-associated antigen CYP1B1.

Studies in radiation therapy for glioblastoma focus mostly on treatment planning. “Currently, we plan our radiation therapy according to preoperative MRI scans,” Dr. Mahajan explained. “Research is ongoing to determine whether other imaging modalities such as positron emission tomography, magnetic resonance spectroscopy, and a variety of high-end MRI techniques might better identify the areas at risk for tumor recurrence.”

Research to improve the current treatment regimen for newly diagnosed glioblastoma patients is also ongoing. A phase III randomized study comparing two doses of temozolomide was recently completed at MD Anderson and other institutions. Those results will be published soon and are expected to further define the standard of care. “With more than 1,000 patients, it is certainly the largest study of glioblastoma that’s ever been done. And it may turn out to be the most important such study because they’ve integrated tissue analysis to look for molecular markers, plus they are looking at measures of quality of life and neurocognitive outcomes,” Dr. de Groot said.

A phase III study investigating the addition of bevacizumab to the standard adjuvant treatment regimen for newly diagnosed patients is underway at MD Anderson and other institutions. Although the results of this trial will not be known for several years, some physicians have begun prescribing bevacizumab off-label and adding it to the standard treatment regimen for newly diagnosed patients. Dr. de Groot said he did not recommend this practice because it is not yet known whether this experimental regimen is effective or alters long-term outcomes and because patients treated with bevacizumab would be ineligible for bevacizumab salvage therapy—or many clinical trials—in the event of a recurrence.

Until ongoing or future trials identify a better treatment, aggressive surgery followed by temozolomide plus radiation therapy and adjuvant temozolomide continues to offer glioblastoma patients the best hope of long-term survival.

For more information, contact Dr. John de Groot at713-792-7255, Dr. Anita Mahajan at 713-563-2350, or Dr. Ganesh Rao at 713-792-2400.

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